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Entry
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- *159555 - LYSINE-SPECIFIC METHYLTRANSFERASE 2A; KMT2A
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*159555</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<nav>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneStructure">Gene Structure</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cytogenetics">Cytogenetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#phenotype">Phenotype</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#pathogenesis">Pathogenesis</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#animalModel">Animal Model</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/159555">Table View</a>
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</li>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div id="mimFloatingLinksMenu">
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<div class="panel panel-primary" style="margin-bottom: 0px; border-radius: 4px 4px 0px 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimExternalLinks">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000118058;t=ENST00000534358" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=4297" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=159555" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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</span>
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</div>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000118058;t=ENST00000534358" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001197104,NM_001412597,NM_005933,XM_006718839,XM_011542829,XM_011542830,XM_011542833,XM_047426963,XM_047426964" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001197104" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=159555" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=01162&isoform_id=01162_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/KMT2A" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/184394,435780,451555,553800,899268,1042097,1042099,1490271,2160396,2558906,3283222,3283224,4007383,4007384,5921389,11072098,11072099,11141513,11141515,11141524,11141526,11141529,11141531,11141533,20162318,28394609,28394611,28394613,28394615,34305635,37362847,56550039,62088596,78182981,119587784,119587785,119587786,119587787,119587788,146345435,193227753,194380712,194381810,308199413,440575921,767970167,767970169,767970175,767970177,1450287425,1631814917,1631814921,1631814925,1818766304,2071024164,2079747284,2090553776,2216795916,2217282925,2217282929,2273708992,2273708995,2315450328,2319117912,2462525308,2462525310,2462525312,2462525314,2462525316,2462525318" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/Q03164" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
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<div style="display: table-row">
|
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
|
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=4297" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000118058;t=ENST00000534358" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=KMT2A" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=KMT2A" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+4297" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/KMT2A" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:4297" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/4297" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr11&hgg_gene=ENST00000648261.1&hgg_start=118436492&hgg_end=118526832&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:7132" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:7132" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=159555[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=159555[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/KMT2A/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000118058" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=KMT2A" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=KMT2A" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=KMT2A" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=KMT2A&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA241" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:7132" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0003862.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:96995" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/KMT2A#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:96995" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/4297/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=4297" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-080521-3" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
|
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
|
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<span class="panel-title">
|
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<span class="small">
|
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
|
|
<div style="display: table-row">
|
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.genome.jp/dbget-bin/get_linkdb?-t+pathway+hsa:4297" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<div><a href="https://reactome.org/content/query?q=KMT2A&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
|
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
|
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<a id="number" class="mim-anchor"></a>
|
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<div class="text-right">
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>SNOMEDCT:</strong> 763618001<br />
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">ICD+</a>
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</div>
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<div>
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<span class="h3">
|
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<span class="mim-font mim-tip-hint" title="Gene description">
|
|
<span class="text-danger"><strong>*</strong></span>
|
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159555
|
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</span>
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</span>
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</div>
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</div>
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<div>
|
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<a id="preferredTitle" class="mim-anchor"></a>
|
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<h3>
|
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<span class="mim-font">
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LYSINE-SPECIFIC METHYLTRANSFERASE 2A; KMT2A
|
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</span>
|
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</h3>
|
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</div>
|
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<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="alternativeTitles" class="mim-anchor"></a>
|
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<div>
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<p>
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<span class="mim-font">
|
|
<em>Alternative titles; symbols</em>
|
|
</span>
|
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</p>
|
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</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; MLL; MLL1<br />
|
|
TRITHORAX, DROSOPHILA, HOMOLOG OF; TRX1<br />
|
|
HRX<br />
|
|
MYELOID/LYMPHOID LEUKEMIA GENE<br />
|
|
MIXED LINEAGE LEUKEMIA GENE<br />
|
|
ALL1 GENE; ALL1<br />
|
|
CXXC FINGER PROTEIN 7; CXXC7
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
</div>
|
|
<div>
|
|
<br />
|
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</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
|
|
<div>
|
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<p>
|
|
<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<span class="h3 mim-font">
|
|
MLL/AF4 FUSION GENE, INCLUDED
|
|
</span>
|
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</div>
|
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|
<div>
|
|
<span class="h4 mim-font">
|
|
|
|
MLL/ENL FUSION GENE, INCLUDED<br />
|
|
MLL/AF9 FUSION GENE, INCLUDED<br />
|
|
MLL/GMPS FUSION GENE, INCLUDED<br />
|
|
MLL/FBP17 FUSION GENE, INCLUDED<br />
|
|
MLL/LPP FUSION GENE, INCLUDED<br />
|
|
MLL/GPH FUSION GENE, INCLUDED<br />
|
|
MLL/PNUTL1 FUSION GENE, INCLUDED<br />
|
|
MLL/CDK6 FUSION GENE, INCLUDED<br />
|
|
MLL/LASP1 FUSION GENE, INCLUDED<br />
|
|
MLL/GRAF FUSION GENE, INCLUDED<br />
|
|
MLL/ABI1 FUSION GENE, INCLUDED<br />
|
|
MLL/LAF4 FUSION GENE, INCLUDED<br />
|
|
MLL/CBL FUSION GENE, INCLUDED<br />
|
|
MLL/LARG FUSION GENE, INCLUDED<br />
|
|
MLL/AF10 FUSION GENE, INCLUDED<br />
|
|
MLL/AF15q14 FUSION GENE, INCLUDED<br />
|
|
MLL/AF6 FUSION GENE, INCLUDED<br />
|
|
MLL/CIP29 FUSION GENE, INCLUDED<br />
|
|
MLL/SEPT6 FUSION GENE, INCLUDED<br />
|
|
MLL/MAML2 FUSION GENE, INCLUDED<br />
|
|
MLL/KIAA1524 FUSION GENE, INCLUDED<br />
|
|
MLL/MPFYVE FUSION GENE, INCLUDED<br />
|
|
MLL/FRYL FUSION GENE, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
<div>
|
|
<br />
|
|
</div>
|
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</div>
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<div>
|
|
<a id="approvedGeneSymbols" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=KMT2A" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">KMT2A</a></em></strong>
|
|
</span>
|
|
</p>
|
|
</div>
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<div>
|
|
<a id="cytogeneticLocation" class="mim-anchor"></a>
|
|
<p>
|
|
<span class="mim-text-font">
|
|
<strong>
|
|
<em>
|
|
Cytogenetic location: <a href="/geneMap/11/986?start=-3&limit=10&highlight=986">11q23.3</a>
|
|
|
|
Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr11:118436492-118526832&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">11:118,436,492-118,526,832</a> </span>
|
|
</em>
|
|
</strong>
|
|
<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
|
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|
|
|
|
|
|
</span>
|
|
</p>
|
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</div>
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<div>
|
|
<br />
|
|
</div>
|
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<div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<p>The KMT2A gene, or MLL, encodes a DNA-binding protein that methylates histone H3 (see <a href="/entry/602810">602810</a>) lys4 (H3K4) and positively regulates expression of target genes, including multiple HOX genes (see <a href="/entry/142980">142980</a>). MLL is a frequent target for recurrent translocations in acute leukemias that may be characterized as acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Leukemias with translocations involving MLL possess unique clinical and biologic characteristics and are often associated with poor prognosis. MLL rearrangements are found in more than 70% of infant leukemias, whether the immunophenotype is more consistent with ALL or AML6, but are less frequent in leukemias from older children. MLL translocations are also found in approximately 10% of AMLs in adults, as well as in therapy-related leukemias, most often characterized as AML, that develop in patients previously treated with topoisomerase II inhibitors for other malignancies. More than 50 different MLL fusion partners have been identified. Leukemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform hematopoietic cells into leukemia stem cells (<a href="#33" class="mim-tip-reference" title="Krivtsov, A. V., Armstrong, S. A. <strong>MLL translocations, histone modifications and leukaemia stem-cell development.</strong> Nature Rev. Cancer 7: 823-833, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17957188/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17957188</a>] [<a href="https://doi.org/10.1038/nrc2253" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17957188">Krivtsov and Armstrong, 2007</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17957188" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Recurring chromosomal translocations involving chromosome 11q23 have been observed in both acute lymphoid leukemia and acute myeloid leukemia (AML; <a href="/entry/601626">601626</a>), especially acute monoblastic leukemia (AML-M5) and acute myelomonocytic leukemia (AMML-M4). <a href="#53" class="mim-tip-reference" title="Rowley, J. D., Diaz, M. O., Espinosa, R., III, Patel, Y. D., van Melle, E., Ziemin, S., Taillon-Miller, P., Lichter, P., Evans, G. A., Kersey, J. H., Ward, D. C., Domer, P. H., Le Beau, M. M. <strong>Mapping chromosome band 11q23 in human acute leukemia with biotinylated probes: identification of 11q23 translocation breakpoints with a yeast artificial chromosome.</strong> Proc. Nat. Acad. Sci. 87: 9358-9362, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2251277/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2251277</a>] [<a href="https://doi.org/10.1073/pnas.87.23.9358" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2251277">Rowley et al. (1990)</a> demonstrated that the breakpoints in four 11q23 translocations associated with leukemia were contained within a yeast artificial chromosome (YAC) clone bearing the CD3D (<a href="/entry/186790">186790</a>) and CD3G (<a href="/entry/186740">186740</a>) genes. Within this YAC, <a href="#72" class="mim-tip-reference" title="Ziemin-van der Poel, S., McCabe, N. R., Gill, H. J., Espinosa, R., III, Patel, Y., Harden, A., Rubinelli, P., Smith, S. D., Le Beau, M. M., Rowley, J. D., Diaz, M. O. <strong>Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.</strong> Proc. Nat. Acad. Sci. 88: 10735-10739, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 89: 4220 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720549</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1720549">Ziemin-van der Poel et al. (1991)</a> identified a transcription unit spanning the breakpoint junctions of 3 of these translocations, 4;11, 9;11, and 11;19. They described 2 other related transcripts that were upregulated in a translocation cell line. <a href="#72" class="mim-tip-reference" title="Ziemin-van der Poel, S., McCabe, N. R., Gill, H. J., Espinosa, R., III, Patel, Y., Harden, A., Rubinelli, P., Smith, S. D., Le Beau, M. M., Rowley, J. D., Diaz, M. O. <strong>Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.</strong> Proc. Nat. Acad. Sci. 88: 10735-10739, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 89: 4220 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720549</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1720549">Ziemin-van der Poel et al. (1991)</a> named the gene MLL for myeloid/lymphoid, or mixed lineage, leukemia. <a href="#10" class="mim-tip-reference" title="Cimino, G., Moir, D. T., Canaani, O., Williams, K., Crist, W. M., Katzav, S., Cannizzaro, L., Lange, B., Nowell, P. C., Croce, C. M., Canaani, E. <strong>Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations.</strong> Cancer Res. 51: 6712-6714, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1835902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1835902</a>]" pmid="1835902">Cimino et al. (1991)</a> identified the same gene and called it ALL1. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2251277+1720549+1835902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#22" class="mim-tip-reference" title="Gu, Y., Nakamura, T., Alder, H., Prasad, R., Canaani, O., Cimino, G., Croce, C. M., Canaani, E. <strong>The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.</strong> Cell 71: 701-708, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423625</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90603-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423625">Gu et al. (1992)</a> determined that the ALL1 gene encodes a protein of more than 3,910 amino acids containing 3 regions with homology to sequences within the Drosophila 'trithorax' gene, including cysteine-rich regions that can be folded into 6 zinc finger-like domains. <a href="#64" class="mim-tip-reference" title="Tkachuk, D. C., Kohler, S., Cleary, M. L. <strong>Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.</strong> Cell 71: 691-700, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423624</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423624">Tkachuk et al. (1992)</a> showed that the ALL1 gene, which they referred to as HRX (for 'homolog of trithorax'), codes for a 431-kD protein. <a href="#14" class="mim-tip-reference" title="Djabali, M., Selleri, L., Parry, P., Bower, M., Young, B. D., Evans, G. A. <strong>A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.</strong> Nature Genet. 2: 113-118, 1992. Note: Erratum: Nature Genet. 4: 431 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303259</a>] [<a href="https://doi.org/10.1038/ng1092-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303259">Djabali et al. (1992)</a> also cloned an 11.5-kb transcript spanning the 11q23 translocation breakpoint. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1423625+1303259+1423624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#47" class="mim-tip-reference" title="Parry, P., Djabali, M., Bower, M., Khristich, J., Waterman, M., Gibbons, B., Young, B. D., Evans, G. <strong>Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.</strong> Proc. Nat. Acad. Sci. 90: 4738-4742, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506328</a>] [<a href="https://doi.org/10.1073/pnas.90.10.4738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506328">Parry et al. (1993)</a> showed that the sequence of a partial TRX1 cDNA contained an open reading frame encoding 1,012 amino acids with extensive homology to the Drosophila trithorax protein, particularly in the zinc finger-like domains. The TRX1 gene appears to be unique in the human genome and has been conserved during evolution. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Butler, L. H., Slany, R., Cui, X., Cleary, M. L., Mason, D. Y. <strong>The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures.</strong> Blood 89: 3361-3370, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9129043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9129043</a>]" pmid="9129043">Butler et al. (1997)</a> analyzed the distribution and localization of HRX proteins in cell lines and human tissues, using both polyclonal and monoclonal antibodies. Immunocytochemical analysis showed a punctate distribution of wildtype and chimeric HRX proteins within cell nuclei, suggesting that HRX localizes to nuclear structures in cells with and without 11q23 translocations. Nuclear staining was found in the majority of tissues studied, with the strongest reactivity in cerebral cortex, kidney, thyroid, and lymphoid tissues. Thus, <a href="#7" class="mim-tip-reference" title="Butler, L. H., Slany, R., Cui, X., Cleary, M. L., Mason, D. Y. <strong>The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures.</strong> Blood 89: 3361-3370, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9129043/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9129043</a>]" pmid="9129043">Butler et al. (1997)</a> concluded that HRX is widely expressed in most cell types, including hematopoietic cells, a finding that precludes an immunocytochemical approach for diagnosis of leukemias bearing 11q23 structural abnormalities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9129043" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using qRT-PCR analysis in mouse retina, <a href="#5" class="mim-tip-reference" title="Brightman, D. S., Grant, R. L., Ruzycki, P. A., Suzuki, R., Henning, A. K., Chen, S. <strong>MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.</strong> Sci. Rep. 8: 11902, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30093671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30093671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30093671[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-018-30355-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30093671">Brightman et al. (2018)</a> determined that Mll1 is widely expressed in neural progenitors and in developing and differentiated neurons, particularly in the inner retina. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30093671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#21" class="mim-tip-reference" title="Gu, Y., Cimino, G., Alder, H., Nakamura, T., Prasad, R., Canaani, O., Moir, D. T., Jones, C., Nowell, P. C., Croce, C. M., Canaani, E. <strong>The (4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase.</strong> Proc. Nat. Acad. Sci. 89: 10464-10468, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1438235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1438235</a>] [<a href="https://doi.org/10.1073/pnas.89.21.10464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1438235">Gu et al. (1992)</a> determined that the MLL gene spans approximately 100 kb and contains at least 21 exons. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1438235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The MLL gene maps to chromosome 11q23 (<a href="#72" class="mim-tip-reference" title="Ziemin-van der Poel, S., McCabe, N. R., Gill, H. J., Espinosa, R., III, Patel, Y., Harden, A., Rubinelli, P., Smith, S. D., Le Beau, M. M., Rowley, J. D., Diaz, M. O. <strong>Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.</strong> Proc. Nat. Acad. Sci. 88: 10735-10739, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 89: 4220 only, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720549</a>] [<a href="https://doi.org/10.1073/pnas.88.23.10735" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1720549">Ziemin-van der Poel et al., 1991</a>; <a href="#10" class="mim-tip-reference" title="Cimino, G., Moir, D. T., Canaani, O., Williams, K., Crist, W. M., Katzav, S., Cannizzaro, L., Lange, B., Nowell, P. C., Croce, C. M., Canaani, E. <strong>Cloning of ALL-1, the locus involved in leukemias with the t(4;11)(q21;q23), t(9;11)(p22;q23), and t(11;19)(q23;p13) chromosome translocations.</strong> Cancer Res. 51: 6712-6714, 1991.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1835902/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1835902</a>]" pmid="1835902">Cimino et al., 1991</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1720549+1835902" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#41" class="mim-tip-reference" title="Milne, T. A., Briggs, S. D., Brock, H. W., Martin, M. E., Gibbs, D., Allis, C. D., Hess, J. L. <strong>MLL targets SET domain methyltransferase activity to Hox gene promoters.</strong> Molec. Cell 10: 1107-1117, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12453418/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12453418</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00741-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12453418">Milne et al. (2002)</a> showed that MLL regulates target HOX gene expression through direct binding to promoter sequences. They determined that the MLL SET domain is a histone H3 (see <a href="/entry/601128">601128</a>) lys4 (K4)-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity was found to be associated with HOX gene activation and H3 K4 methylation at cis regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates HOX expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12453418" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#44" class="mim-tip-reference" title="Nakamura, T., Mori, T., Tada, S., Krajewski, W., Rozovskaia, T., Wassell, R., Dubois, G., Mazo, A., Croce, C. M., Canaani, E. <strong>ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation.</strong> Molec. Cell 10: 1119-1128, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12453419/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12453419</a>] [<a href="https://doi.org/10.1016/s1097-2765(02)00740-2" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12453419">Nakamura et al. (2002)</a> found that ALL1 is present within a stable multiprotein supercomplex composed of at least 29 proteins. The majority of the complex proteins are components of transcription complexes, including TFIID (see <a href="/entry/604912">604912</a>). Other components are involved in RNA processing or histone methylation. The authors found that the complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones, and that the H3 K4 methylation activity of the complex is conferred by the ALL1 SET domain. Chromatin immunoprecipitations showed that ALL1 and other complex components examined were bound at the promoter of an active ALL1-dependent HOXA9 gene (<a href="/entry/142956">142956</a>). In parallel, H3 K4 was methylated, and histones H3 and H4 were acetylated at this promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12453419" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The MLL gene encodes a large nuclear protein that is required for the maintenance of HOX gene expression. MLL is cleaved at 2 conserved sites to generate an N-terminal 320-kD fragment (N320) and a C-terminal 180-kD fragment (C180), which heterodimerize to stabilize the complex and confer its subnuclear destination. <a href="#26" class="mim-tip-reference" title="Hsieh, J. J.-D., Cheng, E. H.-Y., Korsmeyer, S. J. <strong>Taspase1: a threonine aspartase required for cleavage of MLL and proper HOX gene expression.</strong> Cell 115: 293-303, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14636557/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14636557</a>] [<a href="https://doi.org/10.1016/s0092-8674(03)00816-x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14636557">Hsieh et al. (2003)</a> purified and cloned the protease responsible for cleaving MLL, which they entitled taspase-1 (<a href="/entry/608270">608270</a>). They determined that taspase-1 initiates a class of endopeptidases that utilize an N-terminal threonine as the active-site nucleophile to proteolyze polypeptide substrates following aspartate. RNA interference-mediated knockdown of taspase-1 in HeLa cells resulted in the appearance of unprocessed MLL and the loss of proper HOX gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14636557" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#36" class="mim-tip-reference" title="Lim, D. A., Huang, Y.-C., Swigut, T., Mirick, A. L., Garcia-Verdugo, J. M., Wysocka, J., Ernst, P., Alvarez-Buylla, A. <strong>Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells.</strong> Nature 458: 529-533, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19212323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19212323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19212323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19212323">Lim et al. (2009)</a> showed that Mll1 is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate, and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 (<a href="/entry/100790">100790</a>) and gliogenic Olig2 (<a href="/entry/606386">606386</a>) expression are preserved, but Dlx2 (<a href="/entry/126255">126255</a>), a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wildtype subventricular zone cells, Mash1, Olig2, and Dlx2 loci have high levels of histone-3 trimethylated at lys4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2 is bivalently marked by both H3K4me3 and H3K27me3, and the Dlx2 gene fails to properly activate. <a href="#36" class="mim-tip-reference" title="Lim, D. A., Huang, Y.-C., Swigut, T., Mirick, A. L., Garcia-Verdugo, J. M., Wysocka, J., Ernst, P., Alvarez-Buylla, A. <strong>Chromatin remodelling factor Mll1 is essential for neurogenesis from postnatal neural stem cells.</strong> Nature 458: 529-533, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19212323/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19212323</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19212323[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07726" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19212323">Lim et al. (2009)</a> concluded that their data supported a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19212323" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Liu, H., Takeda, S., Kumar, R., Westergard, T. D., Brown, E. J., Pandita, T. K., Cheng, E. H.-Y., Hsieh, J. J.-D. <strong>Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.</strong> Nature 467: 343-346, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818375">Liu et al. (2010)</a> assigned MLL as a novel effector in the mammalian S-phase checkpoint network and identified checkpoint dysfunction as an underlying mechanism of MLL leukemias. MLL is phosphorylated at ser516 by ATR (<a href="/entry/601215">601215</a>) in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase (see <a href="/entry/601436">601436</a>), leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine-4 at late replication origins, and inhibits the loading of CDC45 (<a href="/entry/603465">603465</a>) to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll-null mouse embryonic fibroblasts with wildtype but not S516A or delta-SET mutant MLL rescued the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP (<a href="/entry/600140">600140</a>) knockin allele that mimics human t(11;16) leukemia showed a severe radioresistant DNA synthesis phenotype. <a href="#37" class="mim-tip-reference" title="Liu, H., Takeda, S., Kumar, R., Westergard, T. D., Brown, E. J., Pandita, T. K., Cheng, E. H.-Y., Hsieh, J. J.-D. <strong>Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.</strong> Nature 467: 343-346, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818375">Liu et al. (2010)</a> demonstrated that MLL fusions function as dominant-negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wildtype MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, <a href="#37" class="mim-tip-reference" title="Liu, H., Takeda, S., Kumar, R., Westergard, T. D., Brown, E. J., Pandita, T. K., Cheng, E. H.-Y., Hsieh, J. J.-D. <strong>Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint.</strong> Nature 467: 343-346, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20818375/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20818375</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20818375[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature09350" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20818375">Liu et al. (2010)</a> concluded that their results identified MLL as a key constituent of the mammalian DNA damage response pathway and showed that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukemias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20818375" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#71" class="mim-tip-reference" title="Zhu, J., Sammons, M. A., Donahue, G., Dou, X., Vedadi, M., Getlik, M., Barsyte-Lovejoy, D., Al-awar, R., Katona, B. W., Shilatifard, A., Huang, J., Hua, X., Arrowsmith, C. H., Berger, S. L. <strong>Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.</strong> Nature 525: 206-211, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26331536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26331536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26331536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26331536">Zhu et al. (2015)</a> demonstrated that p53 (<a href="/entry/191170">191170</a>) gain-of-function mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1, MLL2 (KMT2D; <a href="/entry/602113">602113</a>), and acetyltransferase MOZ (KAT6A; <a href="/entry/601408">601408</a>), resulting in genomewide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas showed specific upregulation of MLL1, MLL2, and MOZ in p53 gain-of-function patient-derived tumors, but not in wildtype p53 or p53-null tumors. Cancer cell proliferation was markedly lowered by genetic knockdown of MLL1 or by pharmacologic inhibition of the MLL1 methyltransferase complex. <a href="#71" class="mim-tip-reference" title="Zhu, J., Sammons, M. A., Donahue, G., Dou, X., Vedadi, M., Getlik, M., Barsyte-Lovejoy, D., Al-awar, R., Katona, B. W., Shilatifard, A., Huang, J., Hua, X., Arrowsmith, C. H., Berger, S. L. <strong>Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.</strong> Nature 525: 206-211, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26331536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26331536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26331536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature15251" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26331536">Zhu et al. (2015)</a> concluded that their study revealed a novel chromatin mechanism underlying the progression of tumors with gain-of-function p53, and suggested possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent gain-of-function p53 mutations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26331536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#35" class="mim-tip-reference" title="Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. <strong>Structural basis for activity regulation of MLL family methyltransferases.</strong> Nature 530: 447-452, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26886794">Li et al. (2016)</a> demonstrated that a minimized human RBBP5 (<a href="/entry/600697">600697</a>)-ASH2L (<a href="/entry/604782">604782</a>) heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1; MLL2; MLL3, <a href="/entry/606833">606833</a>; MLL4, <a href="/entry/606834">606834</a>; SET1A, <a href="/entry/611052">611052</a>; SET1B, <a href="/entry/611055">611055</a>). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. <a href="#35" class="mim-tip-reference" title="Li, Y., Han, J., Zhang, Y., Cao, F., Liu, Z., Li, S., Wu, J., Hu, C., Wang, Y., Shuai, J., Chen, J., Cao, L., Li, D., Shi, P., Tian, C., Zhang, J., Dou, Y., Li, G., Chen, Y., Lei, M. <strong>Structural basis for activity regulation of MLL family methyltransferases.</strong> Nature 530: 447-452, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26886794/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26886794</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26886794[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature16952" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="26886794">Li et al. (2016)</a> concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26886794" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Brightman, D. S., Grant, R. L., Ruzycki, P. A., Suzuki, R., Henning, A. K., Chen, S. <strong>MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.</strong> Sci. Rep. 8: 11902, 2018. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/30093671/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">30093671</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=30093671[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41598-018-30355-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="30093671">Brightman et al. (2018)</a> showed that mice with knockout of Mll1 in retinal progenitors display rod/cone dysfunction and deficits in visual signal transmission from photoreceptors to inner neurons. Mll1 deficiency resulted in thinner retinas, particularly affecting the inner layers, due to reduced progenitor cell proliferation and cell cycle progression. Immunostaining combined with RNAseq and histone modification analyses demonstrated that Mll1 deficiency altered retinal cell composition and caused a change in neuron-to-glia ratio. The gene expression profile of horizontal cells (HC) was one of the most severely affected in the knockout retinas, and detailed investigation revealed that Mll1 is indispensable for maintaining HC integrity, including identity, gene expression, and axon network. Mll1 knockout retinas failed to develop normal outer plexiform layer synapses, resulting in defects in visual signal transmission. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=30093671" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#13" class="mim-tip-reference" title="Delgado, R. N., Mansky, B., Ahanger, S. H., Lu, C., Andersen, R. E., Dou, Y., Alvarez-Buylla, A., Lim, D. A. <strong>Maintenance of neural stem cell positional identity by mixed-lineage leukemia 1.</strong> Science 368: 48-53, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32241942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32241942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32241942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aba5960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32241942">Delgado et al. (2020)</a> found that the maintenance of neural stem cell (NSC) positional identity in the murine brain requires a Mll1-dependent epigenetic memory system. After establishment by sonic hedgehog (SHH; <a href="/entry/600725">600725</a>), ventral NSC identity became independent of this morphogen. Even transient Mll1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. <a href="#13" class="mim-tip-reference" title="Delgado, R. N., Mansky, B., Ahanger, S. H., Lu, C., Andersen, R. E., Dou, Y., Alvarez-Buylla, A., Lim, D. A. <strong>Maintenance of neural stem cell positional identity by mixed-lineage leukemia 1.</strong> Science 368: 48-53, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32241942/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32241942</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32241942[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.aba5960" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32241942">Delgado et al. (2020)</a> concluded that spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32241942" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL Fusion Proteins</em></strong></p><p>
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Human ML-2 leukemia cells lack a normal MLL gene and exclusively express an MLL/AF6 (MLLT4; <a href="/entry/159559">159559</a>) fusion protein. <a href="#69" class="mim-tip-reference" title="Yokoyama, A., Somervaille, T. C. P., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M., Cleary, M. L. <strong>The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.</strong> Cell 123: 207-218, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239140</a>] [<a href="https://doi.org/10.1016/j.cell.2005.09.025" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16239140">Yokoyama et al. (2005)</a> showed that MLL/AF6 associated with menin (MEN1; <a href="/entry/613733">613733</a>) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (<a href="/entry/142950">142950</a>), HOXA9 (<a href="/entry/142956">142956</a>), and HOXA10 (<a href="/entry/142957">142957</a>) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; <a href="/entry/159556">159556</a>) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By gel filtration, mass spectrometry, and Western blot analysis of human cell lines, <a href="#46" class="mim-tip-reference" title="Nie, Z., Yan, Z., Chen, E. H., Sechi, S., Ling, C., Zhou, S., Xue, Y., Yang, D., Murray, D., Kanakubo, E., Cleary, M. L., Wang, W. <strong>Novel SWI/SNF chromatin-remodeling complexes contain a mixed-lineage leukemia chromosomal translocation partner.</strong> Molec. Cell. Biol. 23: 2942-2952, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12665591/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12665591</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=12665591[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1128/MCB.23.8.2942-2952.2003" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12665591">Nie et al. (2003)</a> identified unique low-abundance SWI/SWF complexes that contained ENL, several common SWI/SNF subunits, and either BAF250A (ARID1A; <a href="/entry/603024">603024</a>) or BAF250B (ARID1B; <a href="/entry/614556">614556</a>). Western blot analysis of HB(11;19) leukemia cells, which express the oncogenic MLL/ENL fusion protein, revealed that MLL/ENL also interacted with the BAF250B-containing complex. MLL/ENL-containing SWI/SNF complexes coactivated the HOXA7 promoter in a reporter gene assay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12665591" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#27" class="mim-tip-reference" title="Huang, J., Gurung, B., Wan, B., Matkar, S., Veniaminova, N. A., Wan, K., Merchant, J. L., Hua, X., Lei, M. <strong>The same pocket in menin binds both MLL and JUND but has opposite effects on transcription.</strong> Nature 482: 542-546, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22327296/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22327296</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22327296[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10806" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22327296">Huang et al. (2012)</a> reported the crystal structures of human menin (<a href="/entry/613733">613733</a>) in its free form and in complexes with MLL1 or with JUND (<a href="/entry/165162">165162</a>), or with an MLL1-LEDGF (<a href="/entry/603620">603620</a>) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22327296" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><strong><em>MLL Breakpoint Cluster Region</em></strong></p><p>
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The ALL1 gene is rearranged in acute leukemias with interstitial deletions or reciprocal translocations between chromosome 11q23 and chromosomes 1, 4, 6, 9, 10, or 19. <a href="#21" class="mim-tip-reference" title="Gu, Y., Cimino, G., Alder, H., Nakamura, T., Prasad, R., Canaani, O., Moir, D. T., Jones, C., Nowell, P. C., Croce, C. M., Canaani, E. <strong>The (4;11)(q21;q23) chromosome translocations in acute leukemias involve the VDJ recombinase.</strong> Proc. Nat. Acad. Sci. 89: 10464-10468, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1438235/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1438235</a>] [<a href="https://doi.org/10.1073/pnas.89.21.10464" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1438235">Gu et al. (1992)</a> cloned translocation fragments from leukemic cells from t(4;11) and showed clustering of the breakpoints in areas of 7 to 8 kb on both chromosome 4 and 11. Sequencing indicated heptamer and nonamer-like sequences, associated with rearrangements of immunoglobulin and T-cell receptor genes, near the breakpoints. This suggested a direct involvement of the VDJ recombinase in the 11q23 translocations. <a href="#22" class="mim-tip-reference" title="Gu, Y., Nakamura, T., Alder, H., Prasad, R., Canaani, O., Cimino, G., Croce, C. M., Canaani, E. <strong>The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.</strong> Cell 71: 701-708, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423625</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90603-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423625">Gu et al. (1992)</a> determined that the breakpoint cluster region within ALL1 spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1423625+1438235" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="McCabe, N. R., Burnett, R. C., Gill, H. J., Thirman, M. J., Mbangkollo, D., Kipiniak, M., van Melle, E., Ziemin-van der Poel, S., Rowley, J. D., Diaz, M. O. <strong>Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations.</strong> Proc. Nat. Acad. Sci. 89: 11794-11798, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1465401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1465401</a>] [<a href="https://doi.org/10.1073/pnas.89.24.11794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1465401">McCabe et al. (1992)</a> presented evidence that the breakpoints in all the translocations involving 11q23 in leukemia cells, e.g., t(4;11) t(6;11), t(9;11), and t(11;19), are clustered within a 9-kb BamHI genomic region of the MLL gene. <a href="#38" class="mim-tip-reference" title="McCabe, N. R., Burnett, R. C., Gill, H. J., Thirman, M. J., Mbangkollo, D., Kipiniak, M., van Melle, E., Ziemin-van der Poel, S., Rowley, J. D., Diaz, M. O. <strong>Cloning of cDNAs of the MLL gene that detect DNA rearrangements and altered RNA transcripts in human leukemic cells with 11q23 translocations.</strong> Proc. Nat. Acad. Sci. 89: 11794-11798, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1465401/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1465401</a>] [<a href="https://doi.org/10.1073/pnas.89.24.11794" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1465401">McCabe et al. (1992)</a> detected rearrangements of DNA in a fragment of the MLL gene by Southern blot hybridization. <a href="#14" class="mim-tip-reference" title="Djabali, M., Selleri, L., Parry, P., Bower, M., Young, B. D., Evans, G. A. <strong>A trithorax-like gene is interrupted by chromosome 11q23 translocations in acute leukaemias.</strong> Nature Genet. 2: 113-118, 1992. Note: Erratum: Nature Genet. 4: 431 only, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1303259/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1303259</a>] [<a href="https://doi.org/10.1038/ng1092-113" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1303259">Djabali et al. (1992)</a> concluded that most of the breakpoints in infant leukemias with t(4;11) and t(9;11) translocations lie within a 5-kb region. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=1465401+1303259" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using a human TRX1 cDNA as a probe, <a href="#47" class="mim-tip-reference" title="Parry, P., Djabali, M., Bower, M., Khristich, J., Waterman, M., Gibbons, B., Young, B. D., Evans, G. <strong>Structure and expression of the human trithorax-like gene 1 involved in acute leukemias.</strong> Proc. Nat. Acad. Sci. 90: 4738-4742, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506328/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506328</a>] [<a href="https://doi.org/10.1073/pnas.90.10.4738" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506328">Parry et al. (1993)</a> demonstrated that the gene is interrupted in both infant and adult acute myeloid (AML) and lymphoid (ALL) leukemia patients with 11q23 translocations. The structure of the TRX1 gene around the breakpoints show that this part of the human gene is interrupted by 9 introns. As a result of the rearrangement, zinc finger domains are translocated in both ALL and AML patients. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506328" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#60" class="mim-tip-reference" title="Strout, M. P., Marcucci, G., Bloomfield, C. D., Caligiuri, M. A. <strong>The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia.</strong> Proc. Nat. Acad. Sci. 95: 2390-2395, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9482895/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9482895</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9482895[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.5.2390" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9482895">Strout et al. (1998)</a> analyzed the fusion sequences in genomic DNA from 9 patients with AML. Each had a partial tandem repeat spanning exons 2 to 6 of the ALL1 gene on 11q23. The breakpoint in intron 6 occurred in the breakpoint cluster region and the other near the 3-prime end of intron 1. In 7 cases, a distinct point of fusion could not be identified; instead, the sequence gradually diverged from an Alu element in intron 6 to an Alu element in intron 1 through heteroduplex fusion. The results supported the hypothesis that a recombination event between homologous Alu sequences is responsible for the partial tandem duplication of ALL1, probably through an intrastrand slipped-mispairing mechanism, in the majority of AML cases with this defect. This appeared to be the first demonstration identifying Alu element-mediated recombination as a consistent mechanism for gene rearrangement in somatic tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9482895" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/AF4 Fusion Gene</em></strong></p><p>
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<a href="#22" class="mim-tip-reference" title="Gu, Y., Nakamura, T., Alder, H., Prasad, R., Canaani, O., Cimino, G., Croce, C. M., Canaani, E. <strong>The t(4;11) chromosome translocation of human acute leukemias fuses the ALL-1 gene, related to Drosophila trithorax, to the AF-4 gene.</strong> Cell 71: 701-708, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423625/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423625</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90603-a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423625">Gu et al. (1992)</a> determined that the t(4;11) chromosome translocation in leukemia results in 2 reciprocal fusion products coding for chimeric proteins derived from ALL1 and from a gene on chromosome 4 that they termed AF4 (MLLT2; <a href="/entry/159557">159557</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1423625" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL (<a href="/entry/159556">159556</a>). <a href="#43" class="mim-tip-reference" title="Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R. P., Lange, B., Crist, W. M., Nowell, P. C., Croce, C. M., Canaani, E. <strong>Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.</strong> Proc. Nat. Acad. Sci. 90: 4631-4635, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506309</a>] [<a href="https://doi.org/10.1073/pnas.90.10.4631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506309">Nakamura et al. (1993)</a> showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; <a href="/entry/159558">159558</a>) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Independently, <a href="#15" class="mim-tip-reference" title="Domer, P. H., Fakharzadeh, S. S., Chen, C.-S., Jockel, J., Johansen, L., Silverman, G. A., Kersey, J. H., Korsmeyer, S. J. <strong>Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product.</strong> Proc. Nat. Acad. Sci. 90: 7884-7888, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7689231/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7689231</a>] [<a href="https://doi.org/10.1073/pnas.90.16.7884" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7689231">Domer et al. (1993)</a> characterized the MLL/AF4 fusion product generated by the t(4;11) translocation. The sequence of the complete open reading frame for this fusion transcript revealed that the MLL protein is homologous to DNA methyltransferase. In the fusion gene, the 5-prime portion is derived from the MLL gene and the 3-prime portion from the AF4 gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7689231" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#19" class="mim-tip-reference" title="Gale, K. B., Ford, A. M., Repp, R., Borkhardt, A., Keller, C., Eden, O. B., Greaves, M. F. <strong>Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots.</strong> Proc. Nat. Acad. Sci. 94: 13950-13954, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9391133/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9391133</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9391133[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.25.13950" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9391133">Gale et al. (1997)</a> demonstrated that unique or clonotypic MLL-AF4 genomic fusion sequences were detectable in neonatal blood spots from individuals who developed ALL at ages 5 months to 2 years, thus providing unequivocal evidence for a prenatal initiation of acute leukemia in young patients. They stated that common subtypes due to other translocation fusion genes can be expected to have a similar prenatal initiation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9391133" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an infant diagnosed at the age of 3 weeks with ALL after presenting with hepatosplenomegaly and marked leukocytosis, <a href="#50" class="mim-tip-reference" title="Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A. <strong>Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6.</strong> Proc. Nat. Acad. Sci. 99: 4568-4573, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.062066799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930009">Raffini et al. (2002)</a> found a 3-way rearrangement of the MLL, AF4, and CDK6 (<a href="/entry/603368">603368</a>) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11930009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#66" class="mim-tip-reference" title="Wang, Y., Krivtsov, A. V., Sinha, A. U., North, T. E., Goessling, W., Feng, Z., Zon, L. I., Armstrong, S. A. <strong>The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.</strong> Science 327: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20339075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20339075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20339075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1186624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20339075">Wang et al. (2010)</a> studied leukemia stem cells in mouse models of acute myelogenous leukemia induced by either coexpression of the Hoxa9 (<a href="/entry/142956">142956</a>) and Meis1a (<a href="/entry/601739">601739</a>) oncogenes or by the fusion oncoprotein MLL-AF9. The authors showed that the Wnt (see <a href="/entry/164820">164820</a>)/beta-catenin (<a href="/entry/116806">116806</a>) signaling pathway is required for self-renewal of leukemia stem cells that are derived from either hematopoietic stem cells or more differentiated granulocyte-macrophage progenitors. Because the Wnt/beta-catenin pathway is normally active in hematopoietic stem cells but not in granulocyte-macrophage progenitors, <a href="#66" class="mim-tip-reference" title="Wang, Y., Krivtsov, A. V., Sinha, A. U., North, T. E., Goessling, W., Feng, Z., Zon, L. I., Armstrong, S. A. <strong>The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.</strong> Science 327: 1650-1653, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20339075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20339075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20339075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1186624" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20339075">Wang et al. (2010)</a> concluded that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. Beta-catenin is not absolutely required for self-renewal of adult hematopoietic stem cells; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in acute myelogenous leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20339075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/ENL Fusion Gene</em></strong></p><p>
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In studies of a t(11;19)-carrying cell line, <a href="#64" class="mim-tip-reference" title="Tkachuk, D. C., Kohler, S., Cleary, M. L. <strong>Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.</strong> Cell 71: 691-700, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423624</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423624">Tkachuk et al. (1992)</a> identified fusion transcripts expressed from both derivative chromosomes. The more abundant derivative 11 transcript coded for a chimeric protein containing the amino terminal 'AT-hook' motifs of the HRX gene fused to the ENL gene (MLLT1; <a href="/entry/159556">159556</a>) from chromosome 19. (ENL was so named for '11-19 leukemia.') The HRX protein may have effects mediated by DNA binding within the minor groove at AT-rich sites. <a href="#64" class="mim-tip-reference" title="Tkachuk, D. C., Kohler, S., Cleary, M. L. <strong>Involvement of a homolog of Drosophila trithorax by 11q23 chromosomal translocations in acute leukemias.</strong> Cell 71: 691-700, 1992.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1423624/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1423624</a>] [<a href="https://doi.org/10.1016/0092-8674(92)90602-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="1423624">Tkachuk et al. (1992)</a> referred to this type of leukemia as representing the multilineage leukemias rather than mixed lineage leukemias. The cell line carrying the t(11;19) was from a patient with T-cell precursor acute lymphocytic leukemia (<a href="#55" class="mim-tip-reference" title="Smith, S. D., McFall, P., Morgan, R., Link, M., Hecht, F., Cleary, M., Sklar, J. <strong>Long-term growth of malignant thymocytes in vitro.</strong> Blood 73: 2182-2187, 1989.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2786436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2786436</a>]" pmid="2786436">Smith et al., 1989</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=2786436+1423624" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. <a href="#43" class="mim-tip-reference" title="Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R. P., Lange, B., Crist, W. M., Nowell, P. C., Croce, C. M., Canaani, E. <strong>Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.</strong> Proc. Nat. Acad. Sci. 90: 4631-4635, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506309</a>] [<a href="https://doi.org/10.1073/pnas.90.10.4631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506309">Nakamura et al. (1993)</a> showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; <a href="/entry/159558">159558</a>) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/AF9 Fusion Gene</em></strong></p><p>
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Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. <a href="#43" class="mim-tip-reference" title="Nakamura, T., Alder, H., Gu, Y., Prasad, R., Canaani, O., Kamada, N., Gale, R. P., Lange, B., Crist, W. M., Nowell, P. C., Croce, C. M., Canaani, E. <strong>Genes on chromosomes 4, 9, and 19 involved in 11q23 abnormalities in acute leukemia share sequence homology and/or common motifs.</strong> Proc. Nat. Acad. Sci. 90: 4631-4635, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8506309/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8506309</a>] [<a href="https://doi.org/10.1073/pnas.90.10.4631" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8506309">Nakamura et al. (1993)</a> showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; <a href="/entry/159558">159558</a>) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8506309" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The human AF9 gene is one of the most common fusion partner genes with MLL, resulting in the t(9;11)(p22;q23). <a href="#59" class="mim-tip-reference" title="Strissel, P. L., Strick, R., Tomek, R. J., Roe, B. A., Rowley, J. D., Zeleznik-Le, N. J. <strong>DNA structural properties of AF9 are similar to MLL and could act as recombination hot spots resulting in MLL/AF9 translocations and leukemogenesis.</strong> Hum. Molec. Genet. 9: 1671-1679, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10861294/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10861294</a>] [<a href="https://doi.org/10.1093/hmg/9.11.1671" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10861294">Strissel et al. (2000)</a> identified several different structural elements in AF9, including a colocalizing DNA topo II cleavage site and a DNase I hypersensitive (DNase I HS) site. In addition, 2 scaffold-associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border breakpoint regions in 2 leukemic cell lines. The authors thus demonstrated that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR, and they proposed a DNA breakage and repair model for nonhomologous recombination between MLL and its partner genes, particularly AF9. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10861294" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/AF6 Fusion Gene</em></strong></p><p>
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<a href="#49" class="mim-tip-reference" title="Prasad, R., Gu, Y., Alder, H., Nakamura, T., Canaani, O., Saito, H., Huebner, K., Gale, R. P., Nowell, P. C., Kuriyama, K., Miyazaki, Y., Croce, C. M., Canaani, E. <strong>Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation.</strong> Cancer Res. 53: 5624-5628, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8242616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8242616</a>]" pmid="8242616">Prasad et al. (1993)</a> identified AF6 (MLLT4; <a href="/entry/159559">159559</a>) as the fusion partner of MLL in a common translocation, t(6;11)(q27;q23), associated with leukemia. The t(6;11)(q27;q23) translocation results in a chimeric MLL/AF6 protein with a calculated molecular mass of 325 kD. In the chimeric protein, the N-terminal portion of MLL, including 3 AT hook motifs, is fused to all of AF6 except the first 35 amino acids, leaving the Ras-interacting domain and the DHR motif of AF6 intact. By Western blot analysis of transfected COS cells and a human cell line with the t(6;11)(q27;q23) translocation, <a href="#28" class="mim-tip-reference" title="Joh, T., Yamamoto, K., Kagami, Y., Kakuda, H., Sato, T., Yamamoto, T., Takahashi, T., Ueda, R., Kaibuchi, K., Seto, M. <strong>Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11)(q27;q23) leukemia localize in the nucleus.</strong> Oncogene 15: 1681-1687, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9349501/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9349501</a>] [<a href="https://doi.org/10.1038/sj.onc.1201332" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9349501">Joh et al. (1997)</a> found that the MLL/AF6 fusion protein had an apparent molecular mass of 360 kD. Immunolocalization and cell fractionation followed by Western blot analysis indicated that MLL/AF6 was targeted to the nucleus, whereas AF6 itself was cytoplasmic. Mutation analysis indicted that the region of MLL containing AT hook motifs was responsible for the nuclear localization of the chimeric protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8242616+9349501" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/GPH Fusion Gene</em></strong></p><p>
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<a href="#16" class="mim-tip-reference" title="Eguchi, M., Eguchi-Ishimae, M., Seto, M., Morishita, K., Suzuki, K., Ueda, R., Ueda, K., Kamada, N., Greaves, M. <strong>GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24).</strong> Genes Chromosomes Cancer 32: 212-221, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11579461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11579461</a>] [<a href="https://doi.org/10.1002/gcc.1185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11579461">Eguchi et al. (2001)</a> found that the gephyrin gene (GPH; <a href="/entry/603930">603930</a>) can partner with MLL in leukemia associated with the translocation t(11;14)(q23;q24). The child in whom this translocation was discovered showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase II inhibitor VP16. The AT hook motifs and a DNA methyltransferase homology domain of the MLL gene were fused to the C-terminal half of GPH, including a presumed tubulin-binding site and a domain homologous to the E. coli molybdenum cofactor biosynthesis protein. <a href="#16" class="mim-tip-reference" title="Eguchi, M., Eguchi-Ishimae, M., Seto, M., Morishita, K., Suzuki, K., Ueda, R., Ueda, K., Kamada, N., Greaves, M. <strong>GPHN, a novel partner gene fused to MLL in a leukemia with t(11;14)(q23;q24).</strong> Genes Chromosomes Cancer 32: 212-221, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11579461/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11579461</a>] [<a href="https://doi.org/10.1002/gcc.1185" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11579461">Eguchi et al. (2001)</a> suggested that MLL-GPHN may have been generated by the chemotherapeutic agent, followed by error-prone DNA repair via nonhomologous end-joining. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11579461" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/GMPS Fusion Gene</em></strong></p><p>
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In a patient with treatment-related acute myeloid leukemia and the karyotype t(3;11)(q25;q23), <a href="#48" class="mim-tip-reference" title="Pegram, L. D., Megonigal, M. D., Lange, B. J., Nowell, P. C., Rowley, J. D., Rappaport, E. F., Felix, C. A. <strong>t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (guanosine 5-prime monophosphate synthetase) gene.</strong> Blood 96: 4360-4362, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11110714/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11110714</a>]" pmid="11110714">Pegram et al. (2000)</a> identified GMPS (<a href="/entry/600358">600358</a>) to be the partner gene of MLL. The authors stated that GMPS was the first partner gene of MLL to be identified on 3q and the first gene of this type to be found in leukemia-associated translocations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11110714" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/FBP17 Fusion Gene</em></strong></p><p>
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<a href="#18" class="mim-tip-reference" title="Fuchs, U., Rehkamp, G., Haas, O. A., Slany, R., Konig, M., Bojesen, S., Bohle, R. M., Damm-Welk, C., Ludwig, W.-D., Harbott, J., Borkhardt, A. <strong>The human formin-binding protein 17 (FBP17) interacts with sorting nexin, SNX2, and is an MLL-fusion partner in acute myelogeneous leukemia.</strong> Proc. Nat. Acad. Sci. 98: 8756-8761, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11438682/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11438682</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11438682[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.121433898" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11438682">Fuchs et al. (2001)</a> reported fusion of the gene encoding formin-binding protein-17 (FBP17; <a href="/entry/606191">606191</a>) to MLL in a child with acute myelogeneous leukemia and a complex chromosome rearrangement, ins(11;9)(q23;134)inv(11)(q13q23). The fused mRNA was represented by MLL at the 5-prime end and FBP17 at the 3-prime end. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11438682" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/LPP Fusion Gene</em></strong></p><p>
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By FISH and Southern blot analyses, <a href="#12" class="mim-tip-reference" title="Daheron, L., Veinstein, A., Brizard, F., Drabkin, H., Lacotte, L., Guilhot, F., Larsen, C. J., Brizard, A., Roche, J. <strong>Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11)(q28;q23).</strong> Genes Chromosomes Cancer 31: 382-389, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11433529/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11433529</a>] [<a href="https://doi.org/10.1002/gcc.1157" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11433529">Daheron et al. (2001)</a> identified a rearrangement in the mixed lineage leukemia gene due to a novel t(3;11)(q28;q23) translocation in a patient who developed acute myeloid leukemia of the M5 type 3 years after treatment for a follicular lymphoma. Through inverse PCR, they identified the LPP gene (<a href="/entry/600700">600700</a>) on 3q28 as the MLL fusion partner. The breakpoint occurred in intron 8 of MLL and LPP. They found that the MLL/LPP and LPP/MLL predicted proteins contain many of the features present in other MLL rearrangements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11433529" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/PNUTL1 Fusion Gene</em></strong></p><p>
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<a href="#40" class="mim-tip-reference" title="Megonigal, M. D., Rappaport, E. F., Jones, D. H., Williams, T. M., Lovett, B. D., Kelly, K. M., Lerou, P. H., Moulton, T., Budarf, M. L., Felix, C. A. <strong>t(11;22)(q23;q11.2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.</strong> Proc. Nat. Acad. Sci. 95: 6413-6418, 1998. Note: Erratum: Proc. Nat. Acad. Sci. 95: 10344 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9600980[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.11.6413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600980">Megonigal et al. (1998)</a> examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis showed 2 identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detected in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested that a t(11;22)(q23;q11.2) disrupted MLL. <a href="#40" class="mim-tip-reference" title="Megonigal, M. D., Rappaport, E. F., Jones, D. H., Williams, T. M., Lovett, B. D., Kelly, K. M., Lerou, P. H., Moulton, T., Budarf, M. L., Felix, C. A. <strong>t(11;22)(q23;q11.2) in acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes.</strong> Proc. Nat. Acad. Sci. 95: 6413-6418, 1998. Note: Erratum: Proc. Nat. Acad. Sci. 95: 10344 only, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9600980/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9600980</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9600980[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.95.11.6413" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9600980">Megonigal et al. (1998)</a> used panhandle variant PCR to clone the translocation breakpoint and identified a region of 22q11.2 involved in both leukemia and a constitutional disorder. By ligating a single-stranded oligonucleotide that was homologous to known 5-prime MLL genomic sequence to the 5-prime ends of BamHI-digested DNA through a bridging oligonucleotide, they formed the stem-loop template for panhandle variant PCR, which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from 22q11.2 was identical to the human CDCrel (cell division cycle-related) gene (PNUTL1; <a href="/entry/602724">602724</a>) that maps to chromosome 22. Both MLL and PNUTL1 contained homologous CT, TTTGTG, and GAA sequences within a few basepairs of their respective breakpoints, which may have been important in uniting these 2 genes by translocation. RT-PCR amplified an in-frame fusion of MLL exon 7 to PNUTL1 exon 3, indicating that a chimeric mRNA had been transcribed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9600980" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/CDK6 Fusion Gene</em></strong></p><p>
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In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; <a href="/entry/613065">613065</a>) after presenting with hepatosplenomegaly and marked leukocytosis, <a href="#50" class="mim-tip-reference" title="Raffini, L. J., Slater, D. J., Rappaport, E. F., Lo Nigro, L., Cheung, N.-K. V., Biegel, J. A., Nowell, P. C., Lange, B. J., Felix, C. A. <strong>Panhandle and reverse-panhandle PCR enable cloning of der(11) and der(other) genomic breakpoint junctions of MLL translocations and identify complex translocation of MLL, AF-4, and CDK6.</strong> Proc. Nat. Acad. Sci. 99: 4568-4573, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11930009/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11930009</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=11930009[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.062066799" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11930009">Raffini et al. (2002)</a> found a 3-way rearrangement of the MLL, AF4, and CDK6 (<a href="/entry/603368">603368</a>) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11930009" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/LASP1 Fusion Gene</em></strong></p><p>
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<a href="#57" class="mim-tip-reference" title="Strehl, S., Borkhardt, A., Slany, R., Fuchs, U. E., Konig, M., Haas, O. A. <strong>The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21).</strong> Oncogene 22: 157-160, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12527918/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12527918</a>] [<a href="https://doi.org/10.1038/sj.onc.1206042" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12527918">Strehl et al. (2003)</a> identified a new MLL fusion partner on chromosome 17q in the case of an infant with AML-M4 and a t(11;17)(q23;q21) translocation. FISH and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 (<a href="/entry/600328">600328</a>) or MSF (<a href="/entry/604061">604061</a>). RACE revealed an in-frame fusion of MLL to LASP1 (<a href="/entry/602920">602920</a>), a gene that is amplified and overexpressed in breast cancer. The authors stated that retroviral transduction of myeloid progenitors demonstrated that MLL/LASP1 was the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, the others being GRAF (<a href="/entry/605370">605370</a>), ABI1 (<a href="/entry/603050">603050</a>), and FBP17. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12527918" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/LAF4 Fusion Gene</em></strong></p><p>
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<a href="#65" class="mim-tip-reference" title="von Bergh, A. R. M., Beverloo, H. B., Rombout, P., van Wering, E. R., van Weel, M. H., Beverstock, G. C., Kluin, P. M., Slater, R. M., Schuuring, E. <strong>LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia.</strong> Genes Chromosomes Cancer 35: 92-96, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12203795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12203795</a>] [<a href="https://doi.org/10.1002/gcc.10091" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12203795">Von Bergh et al. (2002)</a> identified an MLL/LAF4 (<a href="/entry/601464">601464</a>) fusion gene in an infant with ALL and a t(2;11)(p15;p14) translocation. <a href="#6" class="mim-tip-reference" title="Bruch, J., Wilda, M., Teigler-Schlegel, A., Harbott, J., Borkhardt, A., Metzler, M. <strong>Occurrence of an MLL/LAF4 fusion gene caused by the insertion ins(11;2)(q23;q11.2q11.2) in an infant with acute lymphoblastic leukemia. (Letter)</strong> Genes Chromosomes Cancer 37: 106-109, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12661012/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12661012</a>] [<a href="https://doi.org/10.1002/gcc.10187" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12661012">Bruch et al. (2003)</a> also reported an infant with ALL and an MLL/LAF4 fusion caused by an ins(11;2)(q23;q11.2q11.2) insertion. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12203795+12661012" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/LARG Fusion Gene</em></strong></p><p>
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In a patient with primary acute myeloid leukemia and a complex karyotype, <a href="#32" class="mim-tip-reference" title="Kourlas, P. J., Strout, M. P., Becknell, B., Veronese, M. L., Croce, C. M., Theil, K. S., Krahe, R., Ruutu, T., Knuutila, S., Bloomfield, C. D., Caligiuri, M. A. <strong>Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia.</strong> Proc. Nat. Acad. Sci. 97: 2145-2150, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10681437/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10681437</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10681437[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.040569197" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10681437">Kourlas et al. (2000)</a> found that the 5-prime end of MLL at exon 6 was fused in-frame with the 3-prime end of almost the entire open reading frame of the LARG gene (<a href="/entry/604763">604763</a>), which lies on 11q23. Transcriptional orientation of both genes at 11q23 was found to be from centromere to telomere, consistent with other data that suggested that the MLL/LARG fusion resulted from an interstitial deletion rather than a balanced translocation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10681437" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/CBL Fusion Gene</em></strong></p><p>
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<a href="#17" class="mim-tip-reference" title="Fu, J.-F., Hsu, J.-J., Tang, T.-C., Shih, L.-Y. <strong>Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.</strong> Genes Chromosomes Cancer 37: 214-219, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12696071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12696071</a>] [<a href="https://doi.org/10.1002/gcc.10204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12696071">Fu et al. (2003)</a> found that the CBL gene (<a href="/entry/165360">165360</a>), which lies telomeric to MLL on 11q23, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB M1). MLL exon 6 was fused in-frame with CBL exon 8. The genomic junction region involved the fusion of the 3-prime portion of an Alu element in intron 6 of MLL with the 5-prime portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. The transcriptional orientation of both genes is from centromere to telomere. The results of Southern blot analysis in conjunction with FISH suggested that the MLL/CBL fusion was the result of an interstitial deletion. CBL was the second MLL fusion partner identified on 11q23, the first being the LARG gene. <a href="#17" class="mim-tip-reference" title="Fu, J.-F., Hsu, J.-J., Tang, T.-C., Shih, L.-Y. <strong>Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia.</strong> Genes Chromosomes Cancer 37: 214-219, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12696071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12696071</a>] [<a href="https://doi.org/10.1002/gcc.10204" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12696071">Fu et al. (2003)</a> stated that at least 34 partner genes for MLL had been identified. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12696071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/AF10 Fusion Gene</em></strong></p><p>
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<a href="#62" class="mim-tip-reference" title="Tanabe, S., Bohlander, S. K., Vignon, C. V., Espinosa, R., III, Zhao, N., Strissel, P. L., Zeleznik-Le, N. J., Rowley, J. D. <strong>AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).</strong> Blood 88: 3535-3545, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8896421/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8896421</a>]" pmid="8896421">Tanabe et al. (1996)</a> identified an invins(10;11)(p12;q23q12) and other complex chromosomal rearrangements in a 2-year old boy with acute monoblastic leukemia (AML-M5). Cloning of the proximal 10p breakpoint showed that the MLL gene at chromosome 11q23 was fused to the 3-prime portion of AF10 (MLLT10; <a href="/entry/602409">602409</a>) at chromosome 10p12. Cloning of the telomeric 10p junction revealed that the 5-prime portion of AF10 was fused with the HEAB gene (<a href="/entry/608757">608757</a>). The 5-prime AF10/HEAB fusion transcript was out of frame, while the MLL/3-prime AF10 fusion was in frame. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8896421" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/AF15q14 and MLL/MPFYVE Fusion Genes</em></strong></p><p>
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<a href="#25" class="mim-tip-reference" title="Hayette, S., Tigaud, I., Vanier, A., Martel, S., Corbo, L., Charrin, C., Beillard, E., Deleage, G., Magaud, J. P., Rimokh, R. <strong>AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).</strong> Oncogene 19: 4446-4450, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10980622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10980622</a>] [<a href="https://doi.org/10.1038/sj.onc.1203789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10980622">Hayette et al. (2000)</a> described a 48-year-old man with AML-M4 who was cytogenetically characterized as 46,XY,-3,t(11;15)(q23;q1 4),+mar. The bone marrow was hypercellular, with 80% blast cells. The patient was treated by intensive chemotherapy and died 4 month after diagnosis. The translocation resulted in a in-frame fusion between exon 8 of the MLL gene and exon 10 of the AF15q14 gene (<a href="/entry/609173">609173</a>). The fusion transcript was predicted to encode a 1,503-amino acid protein composed of 1,418 N-terminal amino acids of MLL and 85 C-terminal amino acids of AF15q14, including the bipartite nuclear localization signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10980622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#34" class="mim-tip-reference" title="Kuefer, M. U., Chinwalla, V., Zeleznik-Le, N. J., Behm, F. G., Naeve, C. W., Rakestraw, K. M., Mukatira, S. T., Raimondi, S. C., Morris, S. W. <strong>Characterization of the MLL partner gene AF15q14 involved in t(11;15)(q23;q14).</strong> Oncogene 22: 1418-1424, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12618768/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12618768</a>] [<a href="https://doi.org/10.1038/sj.onc.1206272" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12618768">Kuefer et al. (2003)</a> identified a similar t(11;15)(q23;q14) in a 3-year-old boy with de novo T-cell acute lymphoblastic leukemia. In this translocation, exon 9 of the MLL gene was fused in-frame to exon 12 of the AF15q14 gene. The deduced 1,886-amino acid fusion protein, which contains the N terminus of MLL up to lys1362 fused to the entire C terminus of AF15q14 starting from residue ile1819, has a calculated molecular mass of 208 kD. It differs from the fusion protein described by <a href="#25" class="mim-tip-reference" title="Hayette, S., Tigaud, I., Vanier, A., Martel, S., Corbo, L., Charrin, C., Beillard, E., Deleage, G., Magaud, J. P., Rimokh, R. <strong>AF15q14, a novel partner gene fused to the MLL gene in an acute myeloid leukaemia with a t(11;15)(q23;q14).</strong> Oncogene 19: 4446-4450, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10980622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10980622</a>] [<a href="https://doi.org/10.1038/sj.onc.1203789" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10980622">Hayette et al. (2000)</a> in that it has a coiled-coil domain but no nuclear localization signal. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12618768+10980622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In an 11-year-old boy with AML-M2 and a translocation t(11;15)(q23;q14), <a href="#9" class="mim-tip-reference" title="Chinwalla, V., Chien, A., Odero, M., Neilly, M. B., Zeleznik-Le, N. J., Rowley, J. D. <strong>A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15.</strong> Oncogene 22: 1400-1410, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12618766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12618766</a>] [<a href="https://doi.org/10.1038/sj.onc.1206273" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12618766">Chinwalla et al. (2003)</a> identified MLL-AF15q14 and MLL-MPFYVE (<a href="/entry/619635">619635</a>) fusion transcripts. Both fusion transcripts were in-frame and had the potential to encode novel fusion proteins. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12618766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/CIP29 Fusion Gene</em></strong></p><p>
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In an infant with AML-M4, <a href="#23" class="mim-tip-reference" title="Hashii, Y., Kim, J. Y., Sawada, A., Tokimasa, S., Hiroyuki, F., Ohta, H., Makiko, K., Takihara, Y., Ozono, K., Hara, J. <strong>A novel partner gene CIP29 containing a SAP domain with MLL identified in infantile myelomonocytic leukemia. (Letter)</strong> Leukemia 18: 1546-1548, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15284855/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15284855</a>] [<a href="https://doi.org/10.1038/sj.leu.2403450" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15284855">Hashii et al. (2004)</a> identified a translocation, t(11;12)(q23;q13), in which the coding region of the CIP29 gene (<a href="/entry/610049">610049</a>) was fused in-frame to exon 9 of the MLL gene. The fusion protein had the N-terminal AT hooks and central DNA methyltransferase homology region of MLL fused to nearly all of the CIP29 protein, including the N-terminal SAP domain and 2 C-terminal nuclear localization signals. RT-PCR confirmed expression of the fusion transcript in patient peripheral blood mononuclear cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15284855" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/SEPT6 Fusion Gene</em></strong></p><p>
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<a href="#30" class="mim-tip-reference" title="Kadkol, S. S., Bruno, A., Oh, S., Schmidt, M. L., Lindgren, V. <strong>MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia.</strong> Cancer Genet. Cytogenet. 168: 162-167, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16843108/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16843108</a>] [<a href="https://doi.org/10.1016/j.cancergencyto.2006.02.020" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16843108">Kadkol et al. (2006)</a> described an infant with AML who had a rearrangement between chromosomes 11q23 and Xq24. FISH analysis showed a break in MLL, and RT-PCR analysis confirmed expression of an MLL/SEPT6 (<a href="/entry/300683">300683</a>) fusion transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16843108" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/MAML2 Fusion Gene</em></strong></p><p>
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<a href="#45" class="mim-tip-reference" title="Nemoto, N., Suzukawa, K., Shimizu, S., Shinagawa, A., Takei, N., Taki, T., Hayashi, Y., Kojima, H., Kawakami, Y., Nagasawa, T. <strong>Identification of a novel fusion gene MLL-MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23).</strong> Genes Chromosomes Cancer 46: 813-819, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17551948/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17551948</a>] [<a href="https://doi.org/10.1002/gcc.20467" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17551948">Nemoto et al. (2007)</a> isolated MLL/MAML2 (<a href="/entry/607537">607537</a>) fusion transcripts from secondary AML and myelodysplastic syndrome (MDS) cells with inv(11)(q21q23). RT-PCR revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) resulted in a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the N-terminal part of MLL and 952 amino acids from the C-terminal part of MAML2. The N-terminal part of MAML2, a basic domain that includes a binding site for the NOTCH (see NOTCH1; <a href="/entry/190198">190198</a>) intracellular domain, was deleted in MLL/MAML2. The MLL/MAML2 fusion protein in secondary AML and MDS and the MECT1/MAML2 fusion protein in mucoepithelioid carcinoma, benign Warthin tumor, and clear cell hidradenoma contained the same C-terminal part of MAML2. Reporter gene assays revealed that MLL/MAML2 suppressed HES1 (<a href="/entry/139605">139605</a>) promoter activation by the NOTCH1 intracellular domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17551948" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/GRAF Fusion Gene</em></strong></p><p>
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<a href="#4" class="mim-tip-reference" title="Borkhardt, A., Bojesen, S., Haas, O. A., Fuchs, U., Bartelheimer, D., Loncarevic, I. F., Bohle, R. M., Harbott, J., Repp, R., Jaeger, U., Viehmann, S., Henn, T., Korth, P., Scharr, D., Lampert, F. <strong>The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.</strong> Proc. Nat. Acad. Sci. 97: 9168-9173, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10908648/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10908648</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10908648[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.150079597" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10908648">Borkhardt et al. (2000)</a> found that the GRAF gene (<a href="/entry/605370">605370</a>) was fused with MLL in a unique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocytic leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10908648" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/ABI1 Fusion Gene</em></strong></p><p>
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<a href="#61" class="mim-tip-reference" title="Taki, T., Shibuya, N., Taniwaki, M., Hanada, R., Morishita, K., Bessho, F., Yanagisawa, M., Hayashi, Y. <strong>ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23).</strong> Blood 92: 1125-1130, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9694699/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9694699</a>]" pmid="9694699">Taki et al. (1998)</a> analyzed a patient with AML and t(10;11)(p11.2;q23) and identified, as a fusion partner with MLL, the gene ABI1 (<a href="/entry/603050">603050</a>) on 10p11.2. The ABI1 gene bore no homology with partner genes of MLL previously described, but the ABI1 protein exhibited sequence similarity to protein of homeotic genes, contained several polyproline stretches, and included a Src homology-3 (SH3) domain at the C terminus. The MLL-ABI1 fusion transcript in this patient was formed by an alternatively spliced ABI1. In-frame MLL-ABI1 fusion transcripts combined the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of the alternatively spliced transcript of ABI1. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9694699" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/KIAA1524 Fusion Gene</em></strong></p><p>
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<a href="#11" class="mim-tip-reference" title="Coenen, E. A., Zwaan, C. M., Meyer, C., Marschalek, R., Pieters, R., van der Veken, L. T., Beverloo, H. B., van den Heuvel-Eibrink, M. M. <strong>KIAA1524: a novel MLL translocation partner in acute myeloid leukemia.</strong> Leukemia Res. 35: 133-135, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20943269/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20943269</a>] [<a href="https://doi.org/10.1016/j.leukres.2010.08.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20943269">Coenen et al. (2011)</a> identified the karyotype 46,XX,t(3;11)(q12-13;q23) in bone marrow of a 4-month-old Caucasian girl who presented with the M5 subtype of AML and central nervous system involvement. The patient died 9 weeks after diagnosis. The translocation resulted in fusion of intron 10 of the MLL gene on chromosome 11 to intron 16 of the KIAA1524 gene (<a href="/entry/610643">610643</a>) on chromosome 3. The 2 genes are transcribed in opposite orientations, suggesting that the translocation also required a microinversion. RT-PCR analysis confirmed expression of the fusion transcript, which was predicted to encode a 1,673-amino acid protein containing the N-terminal AT-hook domain, subnuclear localization sites, and methyltransferase domain of MLL fused to the C-terminal coiled-coil domain of KIAA1524. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20943269" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL/FRYL Fusion Gene</em></strong></p><p>
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<a href="#24" class="mim-tip-reference" title="Hayette, S., Cornillet-Lefebvre, P., Tigaud, I., Struski, S., Forissier, S., Berchet, A., Doll, D., Gillot, L., Brahim, W., Delabesse, E., Magaud, J. P., Rimokh, R. <strong>AF4p12, a human homologue to the furry gene of Drosophila, as a novel MLL fusion partner.</strong> Cancer Res. 65: 6521-6525, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16061630/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16061630</a>] [<a href="https://doi.org/10.1158/0008-5472.CAN-05-1325" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16061630">Hayette et al. (2005)</a> identified AF4p12 (FRYL; <a href="/entry/620798">620798</a>) as the fusion partner of MLL in a patient with treatment-related ALL and a t(4;11)(p12;q23) translocation. In-frame fusion between MLL exon 6 and AF4p12 exon 49 resulted in a fusion transcript encoding a putative chimeric protein of 2,074 amino acids, containing 1,362 amino acids from the N-terminal part of MLL and 712 amino acids from the C-terminal part of AF4p12, including the second leucine zipper motif. Luciferase reporter analysis showed that the C-terminal part of AF4p12 fused to MLL displayed transcriptional activation potential when transiently expressed in HeLa cells. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16061630" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>MLL Duplication</em></strong></p><p>
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In a study of patients with acute leukemia but no microscopically visible change at 11q23, <a href="#54" class="mim-tip-reference" title="Schichman, S. A., Caligiuri, M. A., Gu, Y., Strout, M. P., Canaani, E., Bloomfield, C. D., Croce, C. M. <strong>ALL-1 partial duplication in acute leukemia.</strong> Proc. Nat. Acad. Sci. 91: 6236-6239, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8016145/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8016145</a>] [<a href="https://doi.org/10.1073/pnas.91.13.6236" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8016145">Schichman et al. (1994)</a> found molecular evidence of partial duplication of the ALL1 gene. The direct tandem duplication involved a region spanning exons 2 to 6, and a partially duplicated protein gene product was demonstrated. Thus, the ALL1 gene is leukemogenic when it fuses with itself as well as when it fuses with one of the genes on other chromosomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8016145" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In addition to the translocations involving fusion of the ALL1 gene with genes on other chromosomes producing acute lymphoblastic and myelogenous leukemia, the ALL1 gene undergoes self-fusion in acute myeloid leukemias with normal karyotype or trisomy 11. In addition, <a href="#2" class="mim-tip-reference" title="Baffa, R., Negrini, M., Schichman, S. A., Huebner, K., Croce, C. M. <strong>Involvement of the ALL-1 gene in a solid tumor.</strong> Proc. Nat. Acad. Sci. 92: 4922-4926, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7761425/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7761425</a>] [<a href="https://doi.org/10.1073/pnas.92.11.4922" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7761425">Baffa et al. (1995)</a> reported rearrangement of the ALL1 gene in a gastric carcinoma cell line. A complex, 3-way translocation involving chromosomes 1 and 11 and resulting in partial duplication of the ALL1 gene was found. Sequencing of RT-PCR products and Northern blot analysis show that only the partially duplicated ALL1 gene was transcribed, producing an mRNA with exon 8 fused to exon 2. Thus, ALL1 gene rearrangement may play a role in the pathogenesis of some solid malignancies. The absence of the normal transcript in this cell line, in association with loss of heterozygosity on 11q23 seen in solid tumors, suggests that ALL1 is involved in tumorigenesis by a loss-of-function mechanism. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7761425" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Approximately 90% of adult patients with de novo AML and trisomy 11 (+11) as a sole abnormality and 11% of adult patients with de novo AML and normal cytogenetics carry a molecular rearrangement of the ALL1 gene. The rearranged ALL1 gene results from the direct tandem duplication of a portion of ALL1 itself. <a href="#8" class="mim-tip-reference" title="Caligiuri, M. A., Strout, M. P., Oberkircher, A. R., Yu, F., de la Chapelle, A., Bloomfield, C. D. <strong>The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome.</strong> Proc. Nat. Acad. Sci. 94: 3899-3902, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9108076/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9108076</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=9108076[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.94.8.3899" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="9108076">Caligiuri et al. (1997)</a> showed that in cytogenetically normal cases of AML and cases with +11 as the sole cytogenetic abnormality, only 1 chromosome contains the mutated ALL1 allele. Thus, a single mutated ALL1 allele with the partial tandem duplication is sufficient for ALL1-associated leukemogenesis, irrespective of the number of normal genes present. The frequently occurring specific association of +11 and ALL1 gene mutation in the leukemic clone remained unexplained. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9108076" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><strong><em>Detection of MLL Rearrangements</em></strong></p><p>
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<a href="#63" class="mim-tip-reference" title="Thirman, M. J., Gill, H. J., Burnett, R. C., Mbangkollo, D., McCabe, N. R., Kobayashi, H., Ziemin-van der Poel, S., Kaneko, Y., Morgan, R., Sandberg, A. A., Chaganti, R. S. K., Larson, R. A., Le Beau, M. M., Diaz, M. O., Rowley, J. D. <strong>Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.</strong> New Eng. J. Med. 329: 909-914, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8361504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8361504</a>] [<a href="https://doi.org/10.1056/NEJM199309233291302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8361504">Thirman et al. (1993)</a> demonstrated that MLL gene rearrangements can be detected with a single probe and a single restriction-enzyme digest. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8361504" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>The MLL gene spans the breakpoint in translocations involving 11q23, which are responsible for approximately 70% of AML and ALL in infants and are also observed in treatment-related leukemias, especially in patients previously treated with drugs inhibiting topoisomerase II (<a href="#20" class="mim-tip-reference" title="Gibbons, B., Katz, F. E., Ganly, P., Chessells, J. M. <strong>Infant acute lymphoblastic leukaemia with t(11;19).</strong> Brit. J. Haemat. 74: 264-269, 1990.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/2334635/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">2334635</a>] [<a href="https://doi.org/10.1111/j.1365-2141.1990.tb02581.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="2334635">Gibbons et al., 1990</a>; <a href="#63" class="mim-tip-reference" title="Thirman, M. J., Gill, H. J., Burnett, R. C., Mbangkollo, D., McCabe, N. R., Kobayashi, H., Ziemin-van der Poel, S., Kaneko, Y., Morgan, R., Sandberg, A. A., Chaganti, R. S. K., Larson, R. A., Le Beau, M. M., Diaz, M. O., Rowley, J. D. <strong>Rearrangement of the MLL gene in acute lymphoblastic and acute myeloid leukemias with 11q23 chromosomal translocations.</strong> New Eng. J. Med. 329: 909-914, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8361504/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8361504</a>] [<a href="https://doi.org/10.1056/NEJM199309233291302" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8361504">Thirman et al., 1993</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=8361504+2334635" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 15 of 26 AML cases in infants, <a href="#56" class="mim-tip-reference" title="Sorensen, P. H. B., Chen, C.-S., Smith, F. O., Arthur, D. C., Domer, P. H., Bernstein, I. D., Korsmeyer, S. J., Hammond, G. D., Kersey, J. H. <strong>Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes.</strong> J. Clin. Invest. 93: 429-437, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8282816/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8282816</a>] [<a href="https://doi.org/10.1172/JCI116978" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8282816">Sorensen et al. (1994)</a> found rearrangement of the MLL gene at the molecular level. These rearrangements were clustered within an 11-kb region containing 9 exons of the gene. In 14 of the 15 cases with rearrangements, the leukemia was associated with myelomonocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively), both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenotype. Rearrangement also correlated significantly with hyperleukocytosis, another clinical parameter associated with poor outcome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8282816" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#31" class="mim-tip-reference" title="Kobayashi, Y., Yang, J., Shindo, E., Tojo, A., Tani, K., Ozawa, K., Asano, S. <strong>HRX gene rearrangement in acute lymphoblastic leukemia after adjuvant chemotherapy of breast cancer. (Letter)</strong> Blood 82: 3220-3223, 1993.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8219210/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8219210</a>]" pmid="8219210">Kobayashi et al. (1993)</a> described a case of acute lymphoblastic leukemia in a 44-year-old woman after adjuvant chemotherapy of breast cancer; they demonstrated rearrangement of the HRX gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8219210" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Acute lymphoblastic leukemias carrying a chromosomal translocation involving the MLL gene have a particularly poor prognosis. <a href="#1" class="mim-tip-reference" title="Armstrong, S. A., Staunton, J. E., Silverman, L. B., Pieters, R., den Boer, M. L., Minden, M. D., Sallan, S. E., Lander, E. S., Golub, T. R., Korsmeyer, S. J. <strong>MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.</strong> Nature Genet. 30: 41-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11731795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11731795</a>] [<a href="https://doi.org/10.1038/ng765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11731795">Armstrong et al. (2002)</a> showed that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms showed that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. <a href="#1" class="mim-tip-reference" title="Armstrong, S. A., Staunton, J. E., Silverman, L. B., Pieters, R., den Boer, M. L., Minden, M. D., Sallan, S. E., Lander, E. S., Golub, T. R., Korsmeyer, S. J. <strong>MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.</strong> Nature Genet. 30: 41-47, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11731795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11731795</a>] [<a href="https://doi.org/10.1038/ng765" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11731795">Armstrong et al. (2002)</a> proposed that they constitute a distinct disease, denoted as MLL, and showed that the differences in gene expression are robust enough to classify leukemias correctly as MLL versus acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11731795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemias. Epidemiologic studies have suggested that maternal exposure to various substances such as pesticides, marijuana, or an excess of flavonoids (naturally occurring inhibitors of topoisomerase II) might be associated with acute leukemia in infants (<a href="#51" class="mim-tip-reference" title="Ross, J. A., Davies, S. M., Potter, J. D., Robison, L. L. <strong>Epidemiology of childhood leukemia, with a focus on infants.</strong> Epidemiol. Rev. 16: 243-272, 1994.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7713179/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7713179</a>] [<a href="https://doi.org/10.1093/oxfordjournals.epirev.a036153" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7713179">Ross et al., 1994</a>). In search of possible agents inducing infant leukemia, <a href="#58" class="mim-tip-reference" title="Strick, R., Strissel, P. L., Borgers, S., Smith, S. L., Rowley, J. D. <strong>Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.</strong> Proc. Nat. Acad. Sci. 97: 4790-4795, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10758153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10758153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10758153[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.070061297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10758153">Strick et al. (2000)</a> investigated bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines; it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional in vitro experiments demonstrated topoisomerase II (TOP2A; <a href="/entry/126430">126430</a>) as the target of bioflavonoids similar to the 2 chemotherapeutic agents. Based on 20 bioflavonoids tested, <a href="#58" class="mim-tip-reference" title="Strick, R., Strissel, P. L., Borgers, S., Smith, S. L., Rowley, J. D. <strong>Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.</strong> Proc. Nat. Acad. Sci. 97: 4790-4795, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10758153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10758153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10758153[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.070061297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10758153">Strick et al. (2000)</a> identified a common structure essential for topoisomerase II cleavage. The authors' observations supported a 2-stage model of cellular processing of topoisomerase II inhibitors: the first and reversible stage of this cleavage resulted in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage led to cell death because of an accumulation of DNA damage. These results suggested that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia. <a href="#58" class="mim-tip-reference" title="Strick, R., Strissel, P. L., Borgers, S., Smith, S. L., Rowley, J. D. <strong>Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.</strong> Proc. Nat. Acad. Sci. 97: 4790-4795, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10758153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10758153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10758153[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.070061297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10758153">Strick et al. (2000)</a> concluded that although bioflavonoids may be beneficial in certain circumstances, a potential counterbalancing disadvantage is their possible role in causing chromosome translocations leading to leukemia in all age groups, analogous to the translocation forms of AML and ALL after cancer chemotherapy. <a href="#52" class="mim-tip-reference" title="Ross, J. A. <strong>Dietary flavonoids and the MLL gene: a pathway to infant leukemia? (Commentary)</strong> Proc. Nat. Acad. Sci. 97: 4411-4413, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10781030/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10781030</a>] [<a href="https://doi.org/10.1073/pnas.97.9.4411" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10781030">Ross (2000)</a> commented on the observations of <a href="#58" class="mim-tip-reference" title="Strick, R., Strissel, P. L., Borgers, S., Smith, S. L., Rowley, J. D. <strong>Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.</strong> Proc. Nat. Acad. Sci. 97: 4790-4795, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10758153/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10758153</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=10758153[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.070061297" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10758153">Strick et al. (2000)</a> in the context of clinical and epidemiologic findings on childhood leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10758153+7713179+10781030" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#67" class="mim-tip-reference" title="Wang, Z., Smith, K. S., Murphy, M., Piloto, O., Somervaille, T. C. P., Cleary, M. L. <strong>Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.</strong> Nature 455: 1205-1209, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806775</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806775[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07284" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18806775">Wang et al. (2008)</a> reported pharmacologic, physiologic, and genetic studies that demonstrated an oncogenic requirement for glycogen synthase kinase-3 (GSK3; see <a href="/entry/606784">606784</a>) in the maintenance of a specific subtype of poor prognosis human leukemia, genetically defined by mutations of the MLL protooncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL leukemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(KIP1) (<a href="/entry/600778">600778</a>). Inhibition of GSK3 in a preclinical murine model of MLL leukemia provided promising evidence of efficacy and earmarked GSK3 as a candidate cancer drug target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By whole-exome sequencing in 4 patients with Wiedemann-Steiner syndrome (<a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified 3 different heterozygous de novo truncating mutations, all within exon 27 of the MLL gene (<a href="#0001">159555.0001</a>-<a href="#0003">159555.0003</a>) in 3 of the 4 patients. Analysis of MLL in 2 additional patients with a similar phenotype revealed heterozygosity for 2 more de novo truncating mutations (<a href="#0004">159555.0004</a> and <a href="#0005">159555.0005</a>). The variants were confirmed by Sanger sequencing, and none were found in the dbSNP or 1000 Genomes Project databases, in 600 unrelated control exome profiles, or in DNA from the unaffected parents. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 6 unrelated children with WDSTS, <a href="#42" class="mim-tip-reference" title="Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N. J., Tan, T. Y., Yap, P. J. J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.</strong> Clin. Genet. 89: 115-119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25810209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25810209</a>] [<a href="https://doi.org/10.1111/cge.12586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25810209">Miyake et al. (2016)</a> identified 6 different heterozygous mutations in the KMT2A gene (see, e.g., <a href="#0006">159555.0006</a>-<a href="#0008">159555.0008</a>). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were demonstrated to have occurred de novo in 4 of the patients; complete parental DNA was not available for 2 patients. Four of the mutations resulted in nonsense or frameshift mutations, whereas 2 were missense mutations affecting highly conserved residues. Functional studies of the variants and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25810209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#70" class="mim-tip-reference" title="Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. J., Korsmeyer, S. J. <strong>Altered Hox expression and segmental identity in Mll-mutant mice.</strong> Nature 378: 505-508, 1995.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477409</a>] [<a href="https://doi.org/10.1038/378505a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="7477409">Yu et al. (1995)</a> reported that Mll deletion in mice was embryonic lethal. Mll +/- mice had retarded growth, hemopoietic abnormalities, and bidirectional homeotic transformation of the axial skeleton, as well as sternal malformations. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#68" class="mim-tip-reference" title="Yamashita, M., Hirahara, K., Shinnakasu, R., Hosokawa, H., Norikane, S., Kimura, M. Y., Hasegawa, A., Nakayama, T. <strong>Crucial role of MLL for the maintenance of memory T helper type 2 cell responses.</strong> Immunity 24: 611-622, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713978</a>] [<a href="https://doi.org/10.1016/j.immuni.2006.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713978">Yamashita et al. (2006)</a> examined the role of MLL in the immune system using Mll +/- mice. Mll +/- Cd4-positive T cells differentiated normally into antigen-specific effector Th1 and Th2 cells in vitro, but the ability of memory Th2 cells to produce Th2 cytokines was dramatically decreased. Histone methylation and acetylation at Th2 cytokine gene loci was not maintained in Mll +/- memory Th2 cells. Levels of Gata3 (<a href="/entry/131320">131320</a>) mRNA were normal in Mll +/- effector Th2 cells, but they were substantially decreased in Mll +/- memory Th2 cells; mRNA levels of other transcription factors were not affected in Mll +/- memory Th2 cells. Histone modifications of Gata3 were also aberrant in Th2 cell lines in which Mll expression had been knocked down by small interfering RNA. Ovalbumin-induced allergic eosinophilic inflammation was reduced in Mll +/- Th2 cell-transferred mice. <a href="#68" class="mim-tip-reference" title="Yamashita, M., Hirahara, K., Shinnakasu, R., Hosokawa, H., Norikane, S., Kimura, M. Y., Hasegawa, A., Nakayama, T. <strong>Crucial role of MLL for the maintenance of memory T helper type 2 cell responses.</strong> Immunity 24: 611-622, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713978</a>] [<a href="https://doi.org/10.1016/j.immuni.2006.03.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16713978">Yamashita et al. (2006)</a> concluded that MLL plays a crucial role in control of memory Th2 cell responses by maintaining expression of GATA3 and production of Th2 cytokines. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Barabe, F., Kennedy, J. A., Hope, K. J., Dick, J. E. <strong>Modeling the initiation and progression of human acute leukemia in mice.</strong> Science 316: 600-604, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463288</a>] [<a href="https://doi.org/10.1126/science.1139851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17463288">Barabe et al. (2007)</a> demonstrated that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The leukemia-initiating cells retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. <a href="#3" class="mim-tip-reference" title="Barabe, F., Kennedy, J. A., Hope, K. J., Dick, J. E. <strong>Modeling the initiation and progression of human acute leukemia in mice.</strong> Science 316: 600-604, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17463288/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17463288</a>] [<a href="https://doi.org/10.1126/science.1139851" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17463288">Barabe et al. (2007)</a> concluded that the properties of these cells provide a biologic basis for several clinical hallmarks of MLL leukemias. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17463288" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#39" class="mim-tip-reference" title="McMahon, K. A., Hiew, S. Y.-L., Hadjur, S., Veiga-Fernandes, H., Menzel, U., Price, A. J., Kioussis, D., Williams, O., Brady, H. J. M. <strong>Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal.</strong> Cell Stem Cell 1: 338-345, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18371367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18371367</a>] [<a href="https://doi.org/10.1016/j.stem.2007.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18371367">McMahon et al. (2007)</a> found that fetal liver from Mll-knockout mouse embryos showed defects in the hematopoietic stem and progenitor pool, including reductions in long-term and short-term hematopoietic stem cell numbers and a decrease in the quiescent hematopoietic stem cell fraction. Adult mice with conditional Mll knockout had no apparent abnormalities in mature hematopoietic cells in bone marrow, spleen, and thymus. However, conditional Mll-knockout bone marrow cells produced reduced numbers of colony-forming units and showed reduced ability to compete in hematopoietic reconstitution assays. <a href="#39" class="mim-tip-reference" title="McMahon, K. A., Hiew, S. Y.-L., Hadjur, S., Veiga-Fernandes, H., Menzel, U., Price, A. J., Kioussis, D., Williams, O., Brady, H. J. M. <strong>Mll has a critical role in fetal and adult hematopoietic stem cell self-renewal.</strong> Cell Stem Cell 1: 338-345, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18371367/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18371367</a>] [<a href="https://doi.org/10.1016/j.stem.2007.07.002" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18371367">McMahon et al. (2007)</a> concluded that MLL has a critical role in regulating stem cell self-renewal. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18371367" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=159555[MIM]" class="btn btn-default mim-tip-hint" role="button" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122878 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122878;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122878" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 6-year-old boy (WSS-1) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified heterozygosity for a de novo 4-bp deletion (8806_8809del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Val2936Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122879 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122879;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122879" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In an 8-year-old girl (WSS-2) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified heterozygosity for a de novo 1-bp deletion (8267del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Leu2756Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122880 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122880;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122880" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 12-year-old girl (WSS-3) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified heterozygosity for a de novo 1-bp deletion (6913del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Ser2305LeufsTer2). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. The level of MLL transcript in patient skin fibroblasts was reduced in comparison to unrelated healthy controls, indicating nonsense-mediated decay. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0004 WIEDEMANN-STEINER SYNDROME</strong>
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KMT2A, ARG2382TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs387907275 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs387907275;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs387907275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs387907275" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030724" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030724" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030724</a>
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<p>In an 8-year-old boy (WSS-5) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified heterozygosity for a de novo 7144C-T transition in exon 27 of the MLL gene, resulting in an arg2382-to-ter (R2382X) substitution. The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="0005" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0005 WIEDEMANN-STEINER SYNDROME</strong>
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</h4>
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KMT2A, 1-BP DUP, NT4599
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs398122881 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs398122881;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs398122881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs398122881" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000030725" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000030725" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000030725</a>
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</span>
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</div>
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<span class="mim-text-font">
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<p>In a 24-year-old woman (WSS-6) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#29" class="mim-tip-reference" title="Jones, W. D., Dafou, D., McEntagart, M., Woollard, W. J., Elmslie, F. V., Holder-Espinasse, M., Irving, M., Saggar, A. K., Smithson, S., Trembath, R. C., Deshpande, C., Simpson, M. A. <strong>De novo mutations in MLL cause Wiedemann-Steiner syndrome.</strong> Am. J. Hum. Genet. 91: 358-364, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22795537/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22795537</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22795537[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2012.06.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22795537">Jones et al. (2012)</a> identified heterozygosity for a de novo 1-bp duplication (4599dup) in the MLL gene, predicted to cause a frameshift and premature termination (Lys1534Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22795537" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="0006" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0006 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<div style="float: left;">
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KMT2A, ARG2480TER
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555046568 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555046568;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555046568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555046568" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000520124 OR RCV000626313 OR RCV004639263" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000520124, RCV000626313, RCV004639263" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000520124...</a>
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 3-year-old Japanese boy (patient 1) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#42" class="mim-tip-reference" title="Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N. J., Tan, T. Y., Yap, P. J. J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.</strong> Clin. Genet. 89: 115-119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25810209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25810209</a>] [<a href="https://doi.org/10.1111/cge.12586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25810209">Miyake et al. (2016)</a> identified a de novo heterozygous c.7438C-T transition (c.7438C-T, NM_001197104.1) in the KMT2A gene, resulting in an arg2480-to-ter (R2480X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25810209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<a id="0007" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0007 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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<div style="float: left;">
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KMT2A, CYS1189TYR
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</div>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555038125 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555038125;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555038125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555038125" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000626314" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000626314" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000626314</a>
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</span>
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<div>
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<span class="mim-text-font">
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<p>In a 4-year-old Australian boy (patient 3) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#42" class="mim-tip-reference" title="Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N. J., Tan, T. Y., Yap, P. J. J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.</strong> Clin. Genet. 89: 115-119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25810209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25810209</a>] [<a href="https://doi.org/10.1111/cge.12586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25810209">Miyake et al. (2016)</a> identified a de novo heterozygous c.3566G-A transition (c.3566G-A, NM_001197104.1) in the KMT2A gene, resulting in a cys1189-to-tyr (C1189Y) substitution at a highly conserved residue in the CXXC zinc finger domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25810209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<br />
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<div>
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<div>
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<a id="0008" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<strong>.0008 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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KMT2A, 1-BP DEL, 1038A
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</div>
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</span>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs1555035779 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs1555035779;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1555035779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs1555035779" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<span class="mim-text-font">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000626315" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000626315" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000626315</a>
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</span>
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<span class="mim-text-font">
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<p>In a 3-year-old Japanese girl (patient 5) with Wiedemann-Steiner syndrome (WDSTS; <a href="/entry/605130">605130</a>), <a href="#42" class="mim-tip-reference" title="Miyake, N., Tsurusaki, Y., Koshimizu, E., Okamoto, N., Kosho, T., Brown, N. J., Tan, T. Y., Yap, P. J. J., Suzumura, H., Tanaka, T., Nagai, T., Nakashima, M., Saitsu, H., Niikawa, N., Matsumoto, N. <strong>Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.</strong> Clin. Genet. 89: 115-119, 2016.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25810209/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25810209</a>] [<a href="https://doi.org/10.1111/cge.12586" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25810209">Miyake et al. (2016)</a> identified a de novo heterozygous 1-bp deletion (c.1038delA, NM_001197104.1) in the KMT2A gene, predicted to result in a frameshift and premature termination (Val347LeufsTer53) in the N-terminal region of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25810209" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a id="references"class="mim-anchor"></a>
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Armstrong2002" class="mim-anchor"></a>
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Armstrong, S. A., Staunton, J. E., Silverman, L. B., Pieters, R., den Boer, M. L., Minden, M. D., Sallan, S. E., Lander, E. S., Golub, T. R., Korsmeyer, S. J.
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[<a href="https://doi.org/10.1002/gcc.1157" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1002/gcc.10204" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.89.21.10464" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nrc2253" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/sj.onc.1206272" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/cge.12586" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.90.10.4631" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.062066799" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/oxfordjournals.epirev.a036153" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.97.9.4411" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.87.23.9358" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.91.13.6236" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1172/JCI116978" target="_blank">Full Text</a>]
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<strong>The human LASP1 gene is fused to MLL in an acute myeloid leukemia with t(11;17)(q23;q21).</strong>
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<strong>Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia.</strong>
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[<a href="https://doi.org/10.1073/pnas.070061297" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/9.11.1671" target="_blank">Full Text</a>]
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<strong>The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia.</strong>
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[<a href="https://doi.org/10.1073/pnas.95.5.2390" target="_blank">Full Text</a>]
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<strong>AF10 is split by MLL and HEAB, a human homolog to a putative Caenorhabditis elegans ATP/GTP-binding protein in an invins(10;11)(p12;q23q12).</strong>
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<a id="65" class="mim-anchor"></a>
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<a id="von Bergh2002" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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von Bergh, A. R. M., Beverloo, H. B., Rombout, P., van Wering, E. R., van Weel, M. H., Beverstock, G. C., Kluin, P. M., Slater, R. M., Schuuring, E.
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<strong>LAF4, an AF4-related gene, is fused to MLL in infant acute lymphoblastic leukemia.</strong>
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Genes Chromosomes Cancer 35: 92-96, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12203795/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12203795</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12203795" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1002/gcc.10091" target="_blank">Full Text</a>]
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<a id="Wang2010" class="mim-anchor"></a>
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Wang, Y., Krivtsov, A. V., Sinha, A. U., North, T. E., Goessling, W., Feng, Z., Zon, L. I., Armstrong, S. A.
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<strong>The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML.</strong>
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Science 327: 1650-1653, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20339075/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20339075</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20339075[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20339075" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1186624" target="_blank">Full Text</a>]
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<a id="Wang2008" class="mim-anchor"></a>
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<p class="mim-text-font">
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Wang, Z., Smith, K. S., Murphy, M., Piloto, O., Somervaille, T. C. P., Cleary, M. L.
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<strong>Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy.</strong>
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Nature 455: 1205-1209, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18806775/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18806775</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18806775[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18806775" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07284" target="_blank">Full Text</a>]
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<a id="68" class="mim-anchor"></a>
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<a id="Yamashita2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yamashita, M., Hirahara, K., Shinnakasu, R., Hosokawa, H., Norikane, S., Kimura, M. Y., Hasegawa, A., Nakayama, T.
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<strong>Crucial role of MLL for the maintenance of memory T helper type 2 cell responses.</strong>
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Immunity 24: 611-622, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16713978/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16713978</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16713978" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.immuni.2006.03.017" target="_blank">Full Text</a>]
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<a id="69" class="mim-anchor"></a>
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<a id="Yokoyama2005" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yokoyama, A., Somervaille, T. C. P., Smith, K. S., Rozenblatt-Rosen, O., Meyerson, M., Cleary, M. L.
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<strong>The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis.</strong>
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Cell 123: 207-218, 2005.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16239140/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16239140</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16239140" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.cell.2005.09.025" target="_blank">Full Text</a>]
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<a id="70" class="mim-anchor"></a>
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<a id="Yu1995" class="mim-anchor"></a>
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<div class="">
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Yu, B. D., Hess, J. L., Horning, S. E., Brown, G. A. J., Korsmeyer, S. J.
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<strong>Altered Hox expression and segmental identity in Mll-mutant mice.</strong>
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Nature 378: 505-508, 1995.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/7477409/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">7477409</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=7477409" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/378505a0" target="_blank">Full Text</a>]
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<a id="Zhu2015" class="mim-anchor"></a>
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Zhu, J., Sammons, M. A., Donahue, G., Dou, X., Vedadi, M., Getlik, M., Barsyte-Lovejoy, D., Al-awar, R., Katona, B. W., Shilatifard, A., Huang, J., Hua, X., Arrowsmith, C. H., Berger, S. L.
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<strong>Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth.</strong>
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Nature 525: 206-211, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/26331536/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">26331536</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=26331536[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=26331536" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature15251" target="_blank">Full Text</a>]
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<a id="Ziemin-van der Poel1991" class="mim-anchor"></a>
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Ziemin-van der Poel, S., McCabe, N. R., Gill, H. J., Espinosa, R., III, Patel, Y., Harden, A., Rubinelli, P., Smith, S. D., Le Beau, M. M., Rowley, J. D., Diaz, M. O.
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<strong>Identification of a gene, MLL, that spans the breakpoint in 11q23 translocations associated with human leukemias.</strong>
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Proc. Nat. Acad. Sci. 88: 10735-10739, 1991. Note: Erratum: Proc. Nat. Acad. Sci. 89: 4220 only, 1992.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/1720549/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">1720549</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=1720549" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1073/pnas.88.23.10735" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Bao Lige - updated : 04/25/2024
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<span class="mim-text-font">
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Bao Lige - updated : 11/23/2021<br>Ada Hamosh - updated : 09/08/2020<br>Bao Lige - updated : 02/07/2019<br>Cassandra L. Kniffin - updated : 04/24/2018<br>Ada Hamosh - updated : 12/19/2016<br>Ada Hamosh - updated : 11/24/2015<br>Marla J. F. O'Neill - updated : 9/11/2012<br>Patricia A. Hartz - updated : 3/23/2012<br>Ada Hamosh - updated : 3/13/2012<br>Patricia A. Hartz - updated : 8/31/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 4/28/2009<br>Ada Hamosh - updated : 12/30/2008<br>Matthew B. Gross - updated : 10/13/2008<br>Matthew B. Gross - reorganized : 10/13/2008<br>Patricia A. Hartz - updated : 5/2/2008<br>Ada Hamosh - updated : 3/19/2008<br>Paul J. Converse - updated : 10/30/2007<br>Patricia A. Hartz - updated : 8/10/2007<br>Ada Hamosh - updated : 6/4/2007<br>Paul J. Converse - updated : 1/8/2007<br>Patricia A. Hartz - updated : 4/13/2006<br>Patricia A. Hartz - updated : 2/8/2006<br>Patricia A. Hartz - updated : 1/28/2005<br>Patricia A. Hartz - updated : 8/26/2004<br>Stylianos E. Antonarakis - updated : 11/19/2003<br>Stylianos E. Antonarakis - updated : 4/29/2003<br>Jane Kelly - updated : 3/10/2003<br>Victor A. McKusick - updated : 10/14/2002<br>Victor A. McKusick - updated : 2/20/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 11/13/2001<br>Victor A. McKusick - updated : 8/17/2001<br>Victor A. McKusick - updated : 4/2/2001<br>George E. Tiller - updated : 9/18/2000<br>Victor A. McKusick - updated : 7/19/2000<br>Wilson H. Y. Lo - updated : 9/22/1999<br>Wilson H. Y. Lo - updated : 7/23/1999<br>Victor A. McKusick - updated : 9/3/1997<br>Victor A. McKusick - updated : 6/18/1997
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Victor A. McKusick : 1/27/1992
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mgross : 04/25/2024
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mgross : 11/23/2021<br>alopez : 09/08/2020<br>carol : 07/24/2020<br>carol : 02/07/2019<br>alopez : 04/27/2018<br>ckniffin : 04/24/2018<br>carol : 12/20/2016<br>alopez : 12/19/2016<br>alopez : 11/24/2015<br>carol : 9/10/2015<br>mgross : 3/14/2014<br>carol : 9/6/2013<br>mgross : 2/5/2013<br>alopez : 1/30/2013<br>carol : 10/9/2012<br>carol : 9/11/2012<br>carol : 8/17/2012<br>terry : 7/6/2012<br>mgross : 3/27/2012<br>mgross : 3/27/2012<br>terry : 3/23/2012<br>alopez : 3/14/2012<br>terry : 3/13/2012<br>joanna : 3/5/2012<br>mgross : 8/31/2011<br>carol : 4/7/2011<br>carol : 2/9/2011<br>terry : 11/3/2010<br>alopez : 10/5/2010<br>terry : 9/29/2010<br>terry : 9/8/2010<br>alopez : 4/21/2010<br>terry : 4/15/2010<br>wwang : 10/13/2009<br>alopez : 5/5/2009<br>terry : 4/28/2009<br>alopez : 12/31/2008<br>terry : 12/30/2008<br>carol : 12/4/2008<br>mgross : 10/13/2008<br>mgross : 10/13/2008<br>mgross : 10/13/2008<br>mgross : 5/2/2008<br>mgross : 3/19/2008<br>terry : 3/19/2008<br>mgross : 10/30/2007<br>terry : 9/14/2007<br>wwang : 8/17/2007<br>terry : 8/10/2007<br>alopez : 6/12/2007<br>terry : 6/4/2007<br>mgross : 1/8/2007<br>mgross : 4/13/2006<br>mgross : 2/8/2006<br>carol : 5/27/2005<br>alopez : 2/7/2005<br>mgross : 1/28/2005<br>mgross : 1/7/2005<br>mgross : 8/26/2004<br>joanna : 3/16/2004<br>terry : 2/20/2004<br>mgross : 11/19/2003<br>alopez : 11/13/2003<br>carol : 11/6/2003<br>carol : 8/14/2003<br>tkritzer : 8/12/2003<br>carol : 7/31/2003<br>tkritzer : 7/30/2003<br>mgross : 4/29/2003<br>tkritzer : 3/27/2003<br>tkritzer : 3/26/2003<br>carol : 3/10/2003<br>tkritzer : 10/17/2002<br>tkritzer : 10/14/2002<br>carol : 4/19/2002<br>carol : 4/18/2002<br>carol : 2/20/2002<br>alopez : 1/16/2002<br>terry : 1/14/2002<br>carol : 11/13/2001<br>carol : 11/13/2001<br>carol : 8/17/2001<br>carol : 4/2/2001<br>alopez : 9/18/2000<br>mcapotos : 7/20/2000<br>mcapotos : 7/19/2000<br>mcapotos : 7/19/2000<br>mcapotos : 7/17/2000<br>mcapotos : 7/11/2000<br>terry : 6/15/2000<br>carol : 9/27/1999<br>carol : 9/22/1999<br>carol : 7/23/1999<br>carol : 2/22/1999<br>terry : 9/8/1997<br>terry : 9/3/1997<br>alopez : 6/18/1997<br>mark : 10/18/1996<br>mark : 6/19/1995<br>mimadm : 12/2/1994<br>carol : 10/20/1994<br>pfoster : 3/30/1994<br>carol : 10/4/1993<br>carol : 9/20/1993
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<strong>*</strong> 159555
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<h3>
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<span class="mim-font">
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LYSINE-SPECIFIC METHYLTRANSFERASE 2A; KMT2A
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MYELOID/LYMPHOID OR MIXED LINEAGE LEUKEMIA GENE; MLL; MLL1<br />
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TRITHORAX, DROSOPHILA, HOMOLOG OF; TRX1<br />
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HRX<br />
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MYELOID/LYMPHOID LEUKEMIA GENE<br />
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MIXED LINEAGE LEUKEMIA GENE<br />
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ALL1 GENE; ALL1<br />
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CXXC FINGER PROTEIN 7; CXXC7
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<div>
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<p>
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<span class="mim-font">
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Other entities represented in this entry:
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</span>
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</p>
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</div>
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<div>
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<span class="h3 mim-font">
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MLL/AF4 FUSION GENE, INCLUDED
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</span>
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</div>
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<div>
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<span class="h4 mim-font">
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MLL/ENL FUSION GENE, INCLUDED<br />
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MLL/AF9 FUSION GENE, INCLUDED<br />
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MLL/GMPS FUSION GENE, INCLUDED<br />
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MLL/FBP17 FUSION GENE, INCLUDED<br />
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MLL/LPP FUSION GENE, INCLUDED<br />
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MLL/GPH FUSION GENE, INCLUDED<br />
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MLL/PNUTL1 FUSION GENE, INCLUDED<br />
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MLL/CDK6 FUSION GENE, INCLUDED<br />
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MLL/LASP1 FUSION GENE, INCLUDED<br />
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MLL/GRAF FUSION GENE, INCLUDED<br />
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MLL/ABI1 FUSION GENE, INCLUDED<br />
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MLL/LAF4 FUSION GENE, INCLUDED<br />
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MLL/CBL FUSION GENE, INCLUDED<br />
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MLL/LARG FUSION GENE, INCLUDED<br />
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MLL/AF10 FUSION GENE, INCLUDED<br />
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MLL/AF15q14 FUSION GENE, INCLUDED<br />
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MLL/AF6 FUSION GENE, INCLUDED<br />
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MLL/CIP29 FUSION GENE, INCLUDED<br />
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MLL/SEPT6 FUSION GENE, INCLUDED<br />
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MLL/MAML2 FUSION GENE, INCLUDED<br />
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MLL/KIAA1524 FUSION GENE, INCLUDED<br />
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MLL/MPFYVE FUSION GENE, INCLUDED<br />
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MLL/FRYL FUSION GENE, INCLUDED
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</span>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: KMT2A</em></strong>
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</span>
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</p>
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>SNOMEDCT:</strong> 763618001;
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: 11q23.3
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Genomic coordinates <span class="small">(GRCh38)</span> : 11:118,436,492-118,526,832 </span>
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</em>
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</strong>
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<span class="small">(from NCBI)</span>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</h4>
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<div>
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<table class="table table-bordered table-condensed small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
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11q23.3
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</span>
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</td>
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<td>
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<span class="mim-font">
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Wiedemann-Steiner syndrome
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</span>
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</td>
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<td>
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<span class="mim-font">
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605130
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</span>
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</td>
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<td>
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<span class="mim-font">
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Autosomal dominant
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</span>
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</td>
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<td>
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<span class="mim-font">
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3
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>TEXT</strong>
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</span>
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</h4>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The KMT2A gene, or MLL, encodes a DNA-binding protein that methylates histone H3 (see 602810) lys4 (H3K4) and positively regulates expression of target genes, including multiple HOX genes (see 142980). MLL is a frequent target for recurrent translocations in acute leukemias that may be characterized as acute myeloid leukemia (AML; 601626), acute lymphoblastic leukemia (ALL), or mixed lineage (biphenotypic) leukemia (MLL). Leukemias with translocations involving MLL possess unique clinical and biologic characteristics and are often associated with poor prognosis. MLL rearrangements are found in more than 70% of infant leukemias, whether the immunophenotype is more consistent with ALL or AML6, but are less frequent in leukemias from older children. MLL translocations are also found in approximately 10% of AMLs in adults, as well as in therapy-related leukemias, most often characterized as AML, that develop in patients previously treated with topoisomerase II inhibitors for other malignancies. More than 50 different MLL fusion partners have been identified. Leukemogenic MLL translocations encode MLL fusion proteins that have lost H3K4 methyltransferase activity. A key feature of MLL fusion proteins is their ability to efficiently transform hematopoietic cells into leukemia stem cells (Krivtsov and Armstrong, 2007). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cloning and Expression</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Recurring chromosomal translocations involving chromosome 11q23 have been observed in both acute lymphoid leukemia and acute myeloid leukemia (AML; 601626), especially acute monoblastic leukemia (AML-M5) and acute myelomonocytic leukemia (AMML-M4). Rowley et al. (1990) demonstrated that the breakpoints in four 11q23 translocations associated with leukemia were contained within a yeast artificial chromosome (YAC) clone bearing the CD3D (186790) and CD3G (186740) genes. Within this YAC, Ziemin-van der Poel et al. (1991) identified a transcription unit spanning the breakpoint junctions of 3 of these translocations, 4;11, 9;11, and 11;19. They described 2 other related transcripts that were upregulated in a translocation cell line. Ziemin-van der Poel et al. (1991) named the gene MLL for myeloid/lymphoid, or mixed lineage, leukemia. Cimino et al. (1991) identified the same gene and called it ALL1. </p><p>Gu et al. (1992) determined that the ALL1 gene encodes a protein of more than 3,910 amino acids containing 3 regions with homology to sequences within the Drosophila 'trithorax' gene, including cysteine-rich regions that can be folded into 6 zinc finger-like domains. Tkachuk et al. (1992) showed that the ALL1 gene, which they referred to as HRX (for 'homolog of trithorax'), codes for a 431-kD protein. Djabali et al. (1992) also cloned an 11.5-kb transcript spanning the 11q23 translocation breakpoint. </p><p>Parry et al. (1993) showed that the sequence of a partial TRX1 cDNA contained an open reading frame encoding 1,012 amino acids with extensive homology to the Drosophila trithorax protein, particularly in the zinc finger-like domains. The TRX1 gene appears to be unique in the human genome and has been conserved during evolution. </p><p>Butler et al. (1997) analyzed the distribution and localization of HRX proteins in cell lines and human tissues, using both polyclonal and monoclonal antibodies. Immunocytochemical analysis showed a punctate distribution of wildtype and chimeric HRX proteins within cell nuclei, suggesting that HRX localizes to nuclear structures in cells with and without 11q23 translocations. Nuclear staining was found in the majority of tissues studied, with the strongest reactivity in cerebral cortex, kidney, thyroid, and lymphoid tissues. Thus, Butler et al. (1997) concluded that HRX is widely expressed in most cell types, including hematopoietic cells, a finding that precludes an immunocytochemical approach for diagnosis of leukemias bearing 11q23 structural abnormalities. </p><p>Using qRT-PCR analysis in mouse retina, Brightman et al. (2018) determined that Mll1 is widely expressed in neural progenitors and in developing and differentiated neurons, particularly in the inner retina. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Structure</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Gu et al. (1992) determined that the MLL gene spans approximately 100 kb and contains at least 21 exons. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Mapping</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>The MLL gene maps to chromosome 11q23 (Ziemin-van der Poel et al., 1991; Cimino et al., 1991). </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Gene Function</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p>Milne et al. (2002) showed that MLL regulates target HOX gene expression through direct binding to promoter sequences. They determined that the MLL SET domain is a histone H3 (see 601128) lys4 (K4)-specific methyltransferase whose activity is stimulated with acetylated H3 peptides. This methylase activity was found to be associated with HOX gene activation and H3 K4 methylation at cis regulatory sequences in vivo. A leukemogenic MLL fusion protein that activates HOX expression had no effect on histone methylation, suggesting a distinct mechanism for gene regulation by MLL and MLL fusion proteins. </p><p>Nakamura et al. (2002) found that ALL1 is present within a stable multiprotein supercomplex composed of at least 29 proteins. The majority of the complex proteins are components of transcription complexes, including TFIID (see 604912). Other components are involved in RNA processing or histone methylation. The authors found that the complex remodels, acetylates, deacetylates, and methylates nucleosomes and/or free histones, and that the H3 K4 methylation activity of the complex is conferred by the ALL1 SET domain. Chromatin immunoprecipitations showed that ALL1 and other complex components examined were bound at the promoter of an active ALL1-dependent HOXA9 gene (142956). In parallel, H3 K4 was methylated, and histones H3 and H4 were acetylated at this promoter. </p><p>The MLL gene encodes a large nuclear protein that is required for the maintenance of HOX gene expression. MLL is cleaved at 2 conserved sites to generate an N-terminal 320-kD fragment (N320) and a C-terminal 180-kD fragment (C180), which heterodimerize to stabilize the complex and confer its subnuclear destination. Hsieh et al. (2003) purified and cloned the protease responsible for cleaving MLL, which they entitled taspase-1 (608270). They determined that taspase-1 initiates a class of endopeptidases that utilize an N-terminal threonine as the active-site nucleophile to proteolyze polypeptide substrates following aspartate. RNA interference-mediated knockdown of taspase-1 in HeLa cells resulted in the appearance of unprocessed MLL and the loss of proper HOX gene expression. </p><p>Lim et al. (2009) showed that Mll1 is required for neurogenesis in the mouse postnatal brain. Mll1-deficient subventricular zone neural stem cells survive, proliferate, and efficiently differentiate into glial lineages; however, neuronal differentiation is severely impaired. In Mll1-deficient cells, early proneural Mash1 (100790) and gliogenic Olig2 (606386) expression are preserved, but Dlx2 (126255), a key downstream regulator of subventricular zone neurogenesis, is not expressed. Overexpression of Dlx2 can rescue neurogenesis in Mll1-deficient cells. Chromatin immunoprecipitation demonstrates that Dlx2 is a direct target of MLL in subventricular zone cells. In differentiating wildtype subventricular zone cells, Mash1, Olig2, and Dlx2 loci have high levels of histone-3 trimethylated at lys4 (H3K4me3), consistent with their transcription. In contrast, in Mll1-deficient subventricular zone cells, chromatin at Dlx2 is bivalently marked by both H3K4me3 and H3K27me3, and the Dlx2 gene fails to properly activate. Lim et al. (2009) concluded that their data supported a model in which Mll1 is required to resolve key silenced bivalent loci in postnatal neural precursors to the actively transcribed state for the induction of neurogenesis, but not for gliogenesis. </p><p>Liu et al. (2010) assigned MLL as a novel effector in the mammalian S-phase checkpoint network and identified checkpoint dysfunction as an underlying mechanism of MLL leukemias. MLL is phosphorylated at ser516 by ATR (601215) in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase (see 601436), leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine-4 at late replication origins, and inhibits the loading of CDC45 (603465) to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll-null mouse embryonic fibroblasts with wildtype but not S516A or delta-SET mutant MLL rescued the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP (600140) knockin allele that mimics human t(11;16) leukemia showed a severe radioresistant DNA synthesis phenotype. Liu et al. (2010) demonstrated that MLL fusions function as dominant-negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wildtype MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, Liu et al. (2010) concluded that their results identified MLL as a key constituent of the mammalian DNA damage response pathway and showed that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukemias. </p><p>Zhu et al. (2015) demonstrated that p53 (191170) gain-of-function mutants bind to and upregulate chromatin regulatory genes, including the methyltransferases MLL1, MLL2 (KMT2D; 602113), and acetyltransferase MOZ (KAT6A; 601408), resulting in genomewide increases of histone methylation and acetylation. Analysis of The Cancer Genome Atlas showed specific upregulation of MLL1, MLL2, and MOZ in p53 gain-of-function patient-derived tumors, but not in wildtype p53 or p53-null tumors. Cancer cell proliferation was markedly lowered by genetic knockdown of MLL1 or by pharmacologic inhibition of the MLL1 methyltransferase complex. Zhu et al. (2015) concluded that their study revealed a novel chromatin mechanism underlying the progression of tumors with gain-of-function p53, and suggested possibilities for designing combinatorial chromatin-based therapies for treating individual cancers driven by prevalent gain-of-function p53 mutations. </p><p>Li et al. (2016) demonstrated that a minimized human RBBP5 (600697)-ASH2L (604782) heterodimer is the structural unit that interacts with and activates all MLL family histone methyltransferases (MLL1; MLL2; MLL3, 606833; MLL4, 606834; SET1A, 611052; SET1B, 611055). Their structural, biochemical, and computational analyses revealed a 2-step activation mechanism of MLL family proteins. Li et al. (2016) concluded that their findings provided unprecedented insights into the common theme and functional plasticity in complex assembly and activity regulation of MLL family methyltransferases, and also suggested a universal regulation mechanism for most histone methyltransferases. </p><p>Brightman et al. (2018) showed that mice with knockout of Mll1 in retinal progenitors display rod/cone dysfunction and deficits in visual signal transmission from photoreceptors to inner neurons. Mll1 deficiency resulted in thinner retinas, particularly affecting the inner layers, due to reduced progenitor cell proliferation and cell cycle progression. Immunostaining combined with RNAseq and histone modification analyses demonstrated that Mll1 deficiency altered retinal cell composition and caused a change in neuron-to-glia ratio. The gene expression profile of horizontal cells (HC) was one of the most severely affected in the knockout retinas, and detailed investigation revealed that Mll1 is indispensable for maintaining HC integrity, including identity, gene expression, and axon network. Mll1 knockout retinas failed to develop normal outer plexiform layer synapses, resulting in defects in visual signal transmission. </p><p>Delgado et al. (2020) found that the maintenance of neural stem cell (NSC) positional identity in the murine brain requires a Mll1-dependent epigenetic memory system. After establishment by sonic hedgehog (SHH; 600725), ventral NSC identity became independent of this morphogen. Even transient Mll1 inhibition caused a durable loss of ventral identity, resulting in the generation of neurons with the characteristics of dorsal NSCs in vivo. Delgado et al. (2020) concluded that spatial information provided by morphogens can be transitioned to epigenetic mechanisms that maintain regionally distinct developmental programs in the forebrain. </p><p><strong><em>MLL Fusion Proteins</em></strong></p><p>
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Human ML-2 leukemia cells lack a normal MLL gene and exclusively express an MLL/AF6 (MLLT4; 159559) fusion protein. Yokoyama et al. (2005) showed that MLL/AF6 associated with menin (MEN1; 613733) in ML-2 cells. Chromatin immunoprecipitation analysis showed both proteins present on upstream sites of the HOXA7 (142950), HOXA9 (142956), and HOXA10 (142957) promoters. Deletions and point mutations performed in the MLL portion of the MLL/ENL (MLLT1; 159556) fusion protein revealed a high affinity menin-binding motif (RXRFP) near the N terminus. Interaction between oncogenic MLL and menin was required for initiation of MLL-mediated leukemogenesis in mouse stem/progenitor cells, and menin was essential to maintain MLL-associated myeloid transformation. Acute genetic ablation of menin in mice reversed aberrant Hox gene expression mediated by MLL-menin promoter-associated complexes and specifically abrogated differentiation arrest and oncogenic properties of MLL-transformed leukemic blasts. </p><p>By gel filtration, mass spectrometry, and Western blot analysis of human cell lines, Nie et al. (2003) identified unique low-abundance SWI/SWF complexes that contained ENL, several common SWI/SNF subunits, and either BAF250A (ARID1A; 603024) or BAF250B (ARID1B; 614556). Western blot analysis of HB(11;19) leukemia cells, which express the oncogenic MLL/ENL fusion protein, revealed that MLL/ENL also interacted with the BAF250B-containing complex. MLL/ENL-containing SWI/SNF complexes coactivated the HOXA7 promoter in a reporter gene assay. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Biochemical Features</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Huang et al. (2012) reported the crystal structures of human menin (613733) in its free form and in complexes with MLL1 or with JUND (165162), or with an MLL1-LEDGF (603620) heterodimer. These structures showed that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1. </p>
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</span>
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<div>
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<br />
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</div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>Cytogenetics</strong>
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</span>
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</h4>
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</div>
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<span class="mim-text-font">
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<p><strong><em>MLL Breakpoint Cluster Region</em></strong></p><p>
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The ALL1 gene is rearranged in acute leukemias with interstitial deletions or reciprocal translocations between chromosome 11q23 and chromosomes 1, 4, 6, 9, 10, or 19. Gu et al. (1992) cloned translocation fragments from leukemic cells from t(4;11) and showed clustering of the breakpoints in areas of 7 to 8 kb on both chromosome 4 and 11. Sequencing indicated heptamer and nonamer-like sequences, associated with rearrangements of immunoglobulin and T-cell receptor genes, near the breakpoints. This suggested a direct involvement of the VDJ recombinase in the 11q23 translocations. Gu et al. (1992) determined that the breakpoint cluster region within ALL1 spans 8 kb and encompasses several small exons, most of which begin in the same phase of the open reading frame. </p><p>McCabe et al. (1992) presented evidence that the breakpoints in all the translocations involving 11q23 in leukemia cells, e.g., t(4;11) t(6;11), t(9;11), and t(11;19), are clustered within a 9-kb BamHI genomic region of the MLL gene. McCabe et al. (1992) detected rearrangements of DNA in a fragment of the MLL gene by Southern blot hybridization. Djabali et al. (1992) concluded that most of the breakpoints in infant leukemias with t(4;11) and t(9;11) translocations lie within a 5-kb region. </p><p>Using a human TRX1 cDNA as a probe, Parry et al. (1993) demonstrated that the gene is interrupted in both infant and adult acute myeloid (AML) and lymphoid (ALL) leukemia patients with 11q23 translocations. The structure of the TRX1 gene around the breakpoints show that this part of the human gene is interrupted by 9 introns. As a result of the rearrangement, zinc finger domains are translocated in both ALL and AML patients. </p><p>Strout et al. (1998) analyzed the fusion sequences in genomic DNA from 9 patients with AML. Each had a partial tandem repeat spanning exons 2 to 6 of the ALL1 gene on 11q23. The breakpoint in intron 6 occurred in the breakpoint cluster region and the other near the 3-prime end of intron 1. In 7 cases, a distinct point of fusion could not be identified; instead, the sequence gradually diverged from an Alu element in intron 6 to an Alu element in intron 1 through heteroduplex fusion. The results supported the hypothesis that a recombination event between homologous Alu sequences is responsible for the partial tandem duplication of ALL1, probably through an intrastrand slipped-mispairing mechanism, in the majority of AML cases with this defect. This appeared to be the first demonstration identifying Alu element-mediated recombination as a consistent mechanism for gene rearrangement in somatic tissue. </p><p><strong><em>MLL/AF4 Fusion Gene</em></strong></p><p>
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Gu et al. (1992) determined that the t(4;11) chromosome translocation in leukemia results in 2 reciprocal fusion products coding for chimeric proteins derived from ALL1 and from a gene on chromosome 4 that they termed AF4 (MLLT2; 159557). </p><p>Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL (159556). Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. </p><p>Independently, Domer et al. (1993) characterized the MLL/AF4 fusion product generated by the t(4;11) translocation. The sequence of the complete open reading frame for this fusion transcript revealed that the MLL protein is homologous to DNA methyltransferase. In the fusion gene, the 5-prime portion is derived from the MLL gene and the 3-prime portion from the AF4 gene. </p><p>Gale et al. (1997) demonstrated that unique or clonotypic MLL-AF4 genomic fusion sequences were detectable in neonatal blood spots from individuals who developed ALL at ages 5 months to 2 years, thus providing unequivocal evidence for a prenatal initiation of acute leukemia in young patients. They stated that common subtypes due to other translocation fusion genes can be expected to have a similar prenatal initiation. </p><p>In an infant diagnosed at the age of 3 weeks with ALL after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL, AF4, and CDK6 (603368) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. </p><p>Wang et al. (2010) studied leukemia stem cells in mouse models of acute myelogenous leukemia induced by either coexpression of the Hoxa9 (142956) and Meis1a (601739) oncogenes or by the fusion oncoprotein MLL-AF9. The authors showed that the Wnt (see 164820)/beta-catenin (116806) signaling pathway is required for self-renewal of leukemia stem cells that are derived from either hematopoietic stem cells or more differentiated granulocyte-macrophage progenitors. Because the Wnt/beta-catenin pathway is normally active in hematopoietic stem cells but not in granulocyte-macrophage progenitors, Wang et al. (2010) concluded that reactivation of beta-catenin signaling is required for the transformation of progenitor cells by certain oncogenes. Beta-catenin is not absolutely required for self-renewal of adult hematopoietic stem cells; thus, targeting the Wnt/beta-catenin pathway may represent a new therapeutic opportunity in acute myelogenous leukemia. </p><p><strong><em>MLL/ENL Fusion Gene</em></strong></p><p>
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In studies of a t(11;19)-carrying cell line, Tkachuk et al. (1992) identified fusion transcripts expressed from both derivative chromosomes. The more abundant derivative 11 transcript coded for a chimeric protein containing the amino terminal 'AT-hook' motifs of the HRX gene fused to the ENL gene (MLLT1; 159556) from chromosome 19. (ENL was so named for '11-19 leukemia.') The HRX protein may have effects mediated by DNA binding within the minor groove at AT-rich sites. Tkachuk et al. (1992) referred to this type of leukemia as representing the multilineage leukemias rather than mixed lineage leukemias. The cell line carrying the t(11;19) was from a patient with T-cell precursor acute lymphocytic leukemia (Smith et al., 1989). </p><p>Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. </p><p><strong><em>MLL/AF9 Fusion Gene</em></strong></p><p>
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Translocations involving 11q23 in leukemia result in the translocation of zinc finger domains with fusion to other genes on chromosome 4, chromosome 9, or chromosome 19. The gene on chromosome 19 with which it is fused is ENL. Nakamura et al. (1993) showed that the genes with which it is fused on chromosome 4 (AF4) and chromosome 9 (AF9; 159558) show high homology of sequence to ENL. The protein products of the AF4, AF9, and ENL proteins contained nuclear targeting sequences as well as serine-rich and proline-rich regions. </p><p>The human AF9 gene is one of the most common fusion partner genes with MLL, resulting in the t(9;11)(p22;q23). Strissel et al. (2000) identified several different structural elements in AF9, including a colocalizing DNA topo II cleavage site and a DNase I hypersensitive (DNase I HS) site. In addition, 2 scaffold-associated regions (SARs) are located centromeric to the topo II and DNase I HS cleavage sites and border breakpoint regions in 2 leukemic cell lines. The authors thus demonstrated that the patient breakpoint regions of AF9 share the same structural elements as the MLL BCR, and they proposed a DNA breakage and repair model for nonhomologous recombination between MLL and its partner genes, particularly AF9. </p><p><strong><em>MLL/AF6 Fusion Gene</em></strong></p><p>
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Prasad et al. (1993) identified AF6 (MLLT4; 159559) as the fusion partner of MLL in a common translocation, t(6;11)(q27;q23), associated with leukemia. The t(6;11)(q27;q23) translocation results in a chimeric MLL/AF6 protein with a calculated molecular mass of 325 kD. In the chimeric protein, the N-terminal portion of MLL, including 3 AT hook motifs, is fused to all of AF6 except the first 35 amino acids, leaving the Ras-interacting domain and the DHR motif of AF6 intact. By Western blot analysis of transfected COS cells and a human cell line with the t(6;11)(q27;q23) translocation, Joh et al. (1997) found that the MLL/AF6 fusion protein had an apparent molecular mass of 360 kD. Immunolocalization and cell fractionation followed by Western blot analysis indicated that MLL/AF6 was targeted to the nucleus, whereas AF6 itself was cytoplasmic. Mutation analysis indicted that the region of MLL containing AT hook motifs was responsible for the nuclear localization of the chimeric protein. </p><p><strong><em>MLL/GPH Fusion Gene</em></strong></p><p>
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Eguchi et al. (2001) found that the gephyrin gene (GPH; 603930) can partner with MLL in leukemia associated with the translocation t(11;14)(q23;q24). The child in whom this translocation was discovered showed signs of acute undifferentiated leukemia 3 years after intensive chemotherapy that included the topoisomerase II inhibitor VP16. The AT hook motifs and a DNA methyltransferase homology domain of the MLL gene were fused to the C-terminal half of GPH, including a presumed tubulin-binding site and a domain homologous to the E. coli molybdenum cofactor biosynthesis protein. Eguchi et al. (2001) suggested that MLL-GPHN may have been generated by the chemotherapeutic agent, followed by error-prone DNA repair via nonhomologous end-joining. </p><p><strong><em>MLL/GMPS Fusion Gene</em></strong></p><p>
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In a patient with treatment-related acute myeloid leukemia and the karyotype t(3;11)(q25;q23), Pegram et al. (2000) identified GMPS (600358) to be the partner gene of MLL. The authors stated that GMPS was the first partner gene of MLL to be identified on 3q and the first gene of this type to be found in leukemia-associated translocations. </p><p><strong><em>MLL/FBP17 Fusion Gene</em></strong></p><p>
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Fuchs et al. (2001) reported fusion of the gene encoding formin-binding protein-17 (FBP17; 606191) to MLL in a child with acute myelogeneous leukemia and a complex chromosome rearrangement, ins(11;9)(q23;134)inv(11)(q13q23). The fused mRNA was represented by MLL at the 5-prime end and FBP17 at the 3-prime end. </p><p><strong><em>MLL/LPP Fusion Gene</em></strong></p><p>
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By FISH and Southern blot analyses, Daheron et al. (2001) identified a rearrangement in the mixed lineage leukemia gene due to a novel t(3;11)(q28;q23) translocation in a patient who developed acute myeloid leukemia of the M5 type 3 years after treatment for a follicular lymphoma. Through inverse PCR, they identified the LPP gene (600700) on 3q28 as the MLL fusion partner. The breakpoint occurred in intron 8 of MLL and LPP. They found that the MLL/LPP and LPP/MLL predicted proteins contain many of the features present in other MLL rearrangements. </p><p><strong><em>MLL/PNUTL1 Fusion Gene</em></strong></p><p>
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Megonigal et al. (1998) examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis showed 2 identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detected in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested that a t(11;22)(q23;q11.2) disrupted MLL. Megonigal et al. (1998) used panhandle variant PCR to clone the translocation breakpoint and identified a region of 22q11.2 involved in both leukemia and a constitutional disorder. By ligating a single-stranded oligonucleotide that was homologous to known 5-prime MLL genomic sequence to the 5-prime ends of BamHI-digested DNA through a bridging oligonucleotide, they formed the stem-loop template for panhandle variant PCR, which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from 22q11.2 was identical to the human CDCrel (cell division cycle-related) gene (PNUTL1; 602724) that maps to chromosome 22. Both MLL and PNUTL1 contained homologous CT, TTTGTG, and GAA sequences within a few basepairs of their respective breakpoints, which may have been important in uniting these 2 genes by translocation. RT-PCR amplified an in-frame fusion of MLL exon 7 to PNUTL1 exon 3, indicating that a chimeric mRNA had been transcribed. </p><p><strong><em>MLL/CDK6 Fusion Gene</em></strong></p><p>
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In an infant diagnosed at the age of 3 weeks with acute lymphoblastic leukemia (ALL; 613065) after presenting with hepatosplenomegaly and marked leukocytosis, Raffini et al. (2002) found a 3-way rearrangement of the MLL, AF4, and CDK6 (603368) genes. By reverse-panhandle PCR, they identified a breakpoint junction of CDK6 from band 7q21-q22 and MLL intron 9. Thus, the patient had an in-frame CDK6-MLL transcript along with an in-frame MLL-AF4 transcript. </p><p><strong><em>MLL/LASP1 Fusion Gene</em></strong></p><p>
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Strehl et al. (2003) identified a new MLL fusion partner on chromosome 17q in the case of an infant with AML-M4 and a t(11;17)(q23;q21) translocation. FISH and RT-PCR analyses indicated a rearrangement of the MLL gene, but no fusion with previously identified MLL fusion partners at 17q, such as AF17 (600328) or MSF (604061). RACE revealed an in-frame fusion of MLL to LASP1 (602920), a gene that is amplified and overexpressed in breast cancer. The authors stated that retroviral transduction of myeloid progenitors demonstrated that MLL/LASP1 was the fourth known fusion of MLL with a cytoplasmic protein that has no in vitro transformation capability, the others being GRAF (605370), ABI1 (603050), and FBP17. </p><p><strong><em>MLL/LAF4 Fusion Gene</em></strong></p><p>
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Von Bergh et al. (2002) identified an MLL/LAF4 (601464) fusion gene in an infant with ALL and a t(2;11)(p15;p14) translocation. Bruch et al. (2003) also reported an infant with ALL and an MLL/LAF4 fusion caused by an ins(11;2)(q23;q11.2q11.2) insertion. </p><p><strong><em>MLL/LARG Fusion Gene</em></strong></p><p>
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In a patient with primary acute myeloid leukemia and a complex karyotype, Kourlas et al. (2000) found that the 5-prime end of MLL at exon 6 was fused in-frame with the 3-prime end of almost the entire open reading frame of the LARG gene (604763), which lies on 11q23. Transcriptional orientation of both genes at 11q23 was found to be from centromere to telomere, consistent with other data that suggested that the MLL/LARG fusion resulted from an interstitial deletion rather than a balanced translocation. </p><p><strong><em>MLL/CBL Fusion Gene</em></strong></p><p>
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Fu et al. (2003) found that the CBL gene (165360), which lies telomeric to MLL on 11q23, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB M1). MLL exon 6 was fused in-frame with CBL exon 8. The genomic junction region involved the fusion of the 3-prime portion of an Alu element in intron 6 of MLL with the 5-prime portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. The transcriptional orientation of both genes is from centromere to telomere. The results of Southern blot analysis in conjunction with FISH suggested that the MLL/CBL fusion was the result of an interstitial deletion. CBL was the second MLL fusion partner identified on 11q23, the first being the LARG gene. Fu et al. (2003) stated that at least 34 partner genes for MLL had been identified. </p><p><strong><em>MLL/AF10 Fusion Gene</em></strong></p><p>
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Tanabe et al. (1996) identified an invins(10;11)(p12;q23q12) and other complex chromosomal rearrangements in a 2-year old boy with acute monoblastic leukemia (AML-M5). Cloning of the proximal 10p breakpoint showed that the MLL gene at chromosome 11q23 was fused to the 3-prime portion of AF10 (MLLT10; 602409) at chromosome 10p12. Cloning of the telomeric 10p junction revealed that the 5-prime portion of AF10 was fused with the HEAB gene (608757). The 5-prime AF10/HEAB fusion transcript was out of frame, while the MLL/3-prime AF10 fusion was in frame. </p><p><strong><em>MLL/AF15q14 and MLL/MPFYVE Fusion Genes</em></strong></p><p>
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Hayette et al. (2000) described a 48-year-old man with AML-M4 who was cytogenetically characterized as 46,XY,-3,t(11;15)(q23;q1 4),+mar. The bone marrow was hypercellular, with 80% blast cells. The patient was treated by intensive chemotherapy and died 4 month after diagnosis. The translocation resulted in a in-frame fusion between exon 8 of the MLL gene and exon 10 of the AF15q14 gene (609173). The fusion transcript was predicted to encode a 1,503-amino acid protein composed of 1,418 N-terminal amino acids of MLL and 85 C-terminal amino acids of AF15q14, including the bipartite nuclear localization signal. </p><p>Kuefer et al. (2003) identified a similar t(11;15)(q23;q14) in a 3-year-old boy with de novo T-cell acute lymphoblastic leukemia. In this translocation, exon 9 of the MLL gene was fused in-frame to exon 12 of the AF15q14 gene. The deduced 1,886-amino acid fusion protein, which contains the N terminus of MLL up to lys1362 fused to the entire C terminus of AF15q14 starting from residue ile1819, has a calculated molecular mass of 208 kD. It differs from the fusion protein described by Hayette et al. (2000) in that it has a coiled-coil domain but no nuclear localization signal. </p><p>In an 11-year-old boy with AML-M2 and a translocation t(11;15)(q23;q14), Chinwalla et al. (2003) identified MLL-AF15q14 and MLL-MPFYVE (619635) fusion transcripts. Both fusion transcripts were in-frame and had the potential to encode novel fusion proteins. </p><p><strong><em>MLL/CIP29 Fusion Gene</em></strong></p><p>
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In an infant with AML-M4, Hashii et al. (2004) identified a translocation, t(11;12)(q23;q13), in which the coding region of the CIP29 gene (610049) was fused in-frame to exon 9 of the MLL gene. The fusion protein had the N-terminal AT hooks and central DNA methyltransferase homology region of MLL fused to nearly all of the CIP29 protein, including the N-terminal SAP domain and 2 C-terminal nuclear localization signals. RT-PCR confirmed expression of the fusion transcript in patient peripheral blood mononuclear cells. </p><p><strong><em>MLL/SEPT6 Fusion Gene</em></strong></p><p>
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Kadkol et al. (2006) described an infant with AML who had a rearrangement between chromosomes 11q23 and Xq24. FISH analysis showed a break in MLL, and RT-PCR analysis confirmed expression of an MLL/SEPT6 (300683) fusion transcript. </p><p><strong><em>MLL/MAML2 Fusion Gene</em></strong></p><p>
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Nemoto et al. (2007) isolated MLL/MAML2 (607537) fusion transcripts from secondary AML and myelodysplastic syndrome (MDS) cells with inv(11)(q21q23). RT-PCR revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) resulted in a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the N-terminal part of MLL and 952 amino acids from the C-terminal part of MAML2. The N-terminal part of MAML2, a basic domain that includes a binding site for the NOTCH (see NOTCH1; 190198) intracellular domain, was deleted in MLL/MAML2. The MLL/MAML2 fusion protein in secondary AML and MDS and the MECT1/MAML2 fusion protein in mucoepithelioid carcinoma, benign Warthin tumor, and clear cell hidradenoma contained the same C-terminal part of MAML2. Reporter gene assays revealed that MLL/MAML2 suppressed HES1 (139605) promoter activation by the NOTCH1 intracellular domain. </p><p><strong><em>MLL/GRAF Fusion Gene</em></strong></p><p>
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Borkhardt et al. (2000) found that the GRAF gene (605370) was fused with MLL in a unique t(5;11)(q31;q23) that occurred in an infant with juvenile myelomonocytic leukemia. </p><p><strong><em>MLL/ABI1 Fusion Gene</em></strong></p><p>
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Taki et al. (1998) analyzed a patient with AML and t(10;11)(p11.2;q23) and identified, as a fusion partner with MLL, the gene ABI1 (603050) on 10p11.2. The ABI1 gene bore no homology with partner genes of MLL previously described, but the ABI1 protein exhibited sequence similarity to protein of homeotic genes, contained several polyproline stretches, and included a Src homology-3 (SH3) domain at the C terminus. The MLL-ABI1 fusion transcript in this patient was formed by an alternatively spliced ABI1. In-frame MLL-ABI1 fusion transcripts combined the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of the alternatively spliced transcript of ABI1. </p><p><strong><em>MLL/KIAA1524 Fusion Gene</em></strong></p><p>
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Coenen et al. (2011) identified the karyotype 46,XX,t(3;11)(q12-13;q23) in bone marrow of a 4-month-old Caucasian girl who presented with the M5 subtype of AML and central nervous system involvement. The patient died 9 weeks after diagnosis. The translocation resulted in fusion of intron 10 of the MLL gene on chromosome 11 to intron 16 of the KIAA1524 gene (610643) on chromosome 3. The 2 genes are transcribed in opposite orientations, suggesting that the translocation also required a microinversion. RT-PCR analysis confirmed expression of the fusion transcript, which was predicted to encode a 1,673-amino acid protein containing the N-terminal AT-hook domain, subnuclear localization sites, and methyltransferase domain of MLL fused to the C-terminal coiled-coil domain of KIAA1524. </p><p><strong><em>MLL/FRYL Fusion Gene</em></strong></p><p>
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Hayette et al. (2005) identified AF4p12 (FRYL; 620798) as the fusion partner of MLL in a patient with treatment-related ALL and a t(4;11)(p12;q23) translocation. In-frame fusion between MLL exon 6 and AF4p12 exon 49 resulted in a fusion transcript encoding a putative chimeric protein of 2,074 amino acids, containing 1,362 amino acids from the N-terminal part of MLL and 712 amino acids from the C-terminal part of AF4p12, including the second leucine zipper motif. Luciferase reporter analysis showed that the C-terminal part of AF4p12 fused to MLL displayed transcriptional activation potential when transiently expressed in HeLa cells. </p><p><strong><em>MLL Duplication</em></strong></p><p>
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In a study of patients with acute leukemia but no microscopically visible change at 11q23, Schichman et al. (1994) found molecular evidence of partial duplication of the ALL1 gene. The direct tandem duplication involved a region spanning exons 2 to 6, and a partially duplicated protein gene product was demonstrated. Thus, the ALL1 gene is leukemogenic when it fuses with itself as well as when it fuses with one of the genes on other chromosomes. </p><p>In addition to the translocations involving fusion of the ALL1 gene with genes on other chromosomes producing acute lymphoblastic and myelogenous leukemia, the ALL1 gene undergoes self-fusion in acute myeloid leukemias with normal karyotype or trisomy 11. In addition, Baffa et al. (1995) reported rearrangement of the ALL1 gene in a gastric carcinoma cell line. A complex, 3-way translocation involving chromosomes 1 and 11 and resulting in partial duplication of the ALL1 gene was found. Sequencing of RT-PCR products and Northern blot analysis show that only the partially duplicated ALL1 gene was transcribed, producing an mRNA with exon 8 fused to exon 2. Thus, ALL1 gene rearrangement may play a role in the pathogenesis of some solid malignancies. The absence of the normal transcript in this cell line, in association with loss of heterozygosity on 11q23 seen in solid tumors, suggests that ALL1 is involved in tumorigenesis by a loss-of-function mechanism. </p><p>Approximately 90% of adult patients with de novo AML and trisomy 11 (+11) as a sole abnormality and 11% of adult patients with de novo AML and normal cytogenetics carry a molecular rearrangement of the ALL1 gene. The rearranged ALL1 gene results from the direct tandem duplication of a portion of ALL1 itself. Caligiuri et al. (1997) showed that in cytogenetically normal cases of AML and cases with +11 as the sole cytogenetic abnormality, only 1 chromosome contains the mutated ALL1 allele. Thus, a single mutated ALL1 allele with the partial tandem duplication is sufficient for ALL1-associated leukemogenesis, irrespective of the number of normal genes present. The frequently occurring specific association of +11 and ALL1 gene mutation in the leukemic clone remained unexplained. </p><p><strong><em>Detection of MLL Rearrangements</em></strong></p><p>
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Thirman et al. (1993) demonstrated that MLL gene rearrangements can be detected with a single probe and a single restriction-enzyme digest. The ability to detect an MLL gene rearrangement rapidly and reliably, especially in patients with limited material for cytogenetic analysis, should make it possible to identify patients who have a poor prognosis and therefore require aggressive chemotherapy or marrow transplantation. </p>
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<strong>Phenotype</strong>
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<p>The MLL gene spans the breakpoint in translocations involving 11q23, which are responsible for approximately 70% of AML and ALL in infants and are also observed in treatment-related leukemias, especially in patients previously treated with drugs inhibiting topoisomerase II (Gibbons et al., 1990; Thirman et al., 1993). </p><p>In 15 of 26 AML cases in infants, Sorensen et al. (1994) found rearrangement of the MLL gene at the molecular level. These rearrangements were clustered within an 11-kb region containing 9 exons of the gene. In 14 of the 15 cases with rearrangements, the leukemia was associated with myelomonocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively), both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenotype. Rearrangement also correlated significantly with hyperleukocytosis, another clinical parameter associated with poor outcome. </p><p>Kobayashi et al. (1993) described a case of acute lymphoblastic leukemia in a 44-year-old woman after adjuvant chemotherapy of breast cancer; they demonstrated rearrangement of the HRX gene. </p><p>Acute lymphoblastic leukemias carrying a chromosomal translocation involving the MLL gene have a particularly poor prognosis. Armstrong et al. (2002) showed that they have a characteristic, highly distinct gene expression profile that is consistent with an early hematopoietic progenitor expressing select multilineage markers and individual HOX genes. Clustering algorithms showed that lymphoblastic leukemias with MLL translocations can clearly be separated from conventional acute lymphoblastic and acute myelogenous leukemias. Armstrong et al. (2002) proposed that they constitute a distinct disease, denoted as MLL, and showed that the differences in gene expression are robust enough to classify leukemias correctly as MLL versus acute lymphoblastic leukemia or acute myelogenous leukemia. Establishing that MLL is a unique entity is critical, as it mandates the examination of selectively expressed genes for urgently needed molecular targets. </p>
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<strong>Pathogenesis</strong>
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<p>Chromosomal translocations involving the MLL gene occur in about 80% of infant leukemias. Epidemiologic studies have suggested that maternal exposure to various substances such as pesticides, marijuana, or an excess of flavonoids (naturally occurring inhibitors of topoisomerase II) might be associated with acute leukemia in infants (Ross et al., 1994). In search of possible agents inducing infant leukemia, Strick et al. (2000) investigated bioflavonoids, natural substances in food as well as in dietary supplements, that cause site-specific DNA cleavage in the MLL breakpoint cluster region (BCR) in vivo. The MLL BCR DNA cleavage was shown in primary progenitor hematopoietic cells from healthy newborns and adults as well as in cell lines; it colocalized with the MLL BCR cleavage site induced by chemotherapeutic agents, such as etoposide (VP16) and doxorubicin (Dox). Both in vivo and additional in vitro experiments demonstrated topoisomerase II (TOP2A; 126430) as the target of bioflavonoids similar to the 2 chemotherapeutic agents. Based on 20 bioflavonoids tested, Strick et al. (2000) identified a common structure essential for topoisomerase II cleavage. The authors' observations supported a 2-stage model of cellular processing of topoisomerase II inhibitors: the first and reversible stage of this cleavage resulted in DNA repair, but also rarely in chromosome translocations; whereas the second, nonreversible stage led to cell death because of an accumulation of DNA damage. These results suggested that maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocations in utero leading to infant and early childhood leukemia. Strick et al. (2000) concluded that although bioflavonoids may be beneficial in certain circumstances, a potential counterbalancing disadvantage is their possible role in causing chromosome translocations leading to leukemia in all age groups, analogous to the translocation forms of AML and ALL after cancer chemotherapy. Ross (2000) commented on the observations of Strick et al. (2000) in the context of clinical and epidemiologic findings on childhood leukemia. </p><p>Wang et al. (2008) reported pharmacologic, physiologic, and genetic studies that demonstrated an oncogenic requirement for glycogen synthase kinase-3 (GSK3; see 606784) in the maintenance of a specific subtype of poor prognosis human leukemia, genetically defined by mutations of the MLL protooncogene. In contrast to its previously characterized roles in suppression of neoplasia-associated signaling pathways, GSK3 paradoxically supports MLL leukemia cell proliferation and transformation by a mechanism that ultimately involves destabilization of the cyclin-dependent kinase inhibitor p27(KIP1) (600778). Inhibition of GSK3 in a preclinical murine model of MLL leukemia provided promising evidence of efficacy and earmarked GSK3 as a candidate cancer drug target. </p>
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<strong>Molecular Genetics</strong>
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<p>By whole-exome sequencing in 4 patients with Wiedemann-Steiner syndrome (605130), Jones et al. (2012) identified 3 different heterozygous de novo truncating mutations, all within exon 27 of the MLL gene (159555.0001-159555.0003) in 3 of the 4 patients. Analysis of MLL in 2 additional patients with a similar phenotype revealed heterozygosity for 2 more de novo truncating mutations (159555.0004 and 159555.0005). The variants were confirmed by Sanger sequencing, and none were found in the dbSNP or 1000 Genomes Project databases, in 600 unrelated control exome profiles, or in DNA from the unaffected parents. </p><p>In 6 unrelated children with WDSTS, Miyake et al. (2016) identified 6 different heterozygous mutations in the KMT2A gene (see, e.g., 159555.0006-159555.0008). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were demonstrated to have occurred de novo in 4 of the patients; complete parental DNA was not available for 2 patients. Four of the mutations resulted in nonsense or frameshift mutations, whereas 2 were missense mutations affecting highly conserved residues. Functional studies of the variants and studies of patient cells were not performed. </p>
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<p>Yu et al. (1995) reported that Mll deletion in mice was embryonic lethal. Mll +/- mice had retarded growth, hemopoietic abnormalities, and bidirectional homeotic transformation of the axial skeleton, as well as sternal malformations. </p><p>Yamashita et al. (2006) examined the role of MLL in the immune system using Mll +/- mice. Mll +/- Cd4-positive T cells differentiated normally into antigen-specific effector Th1 and Th2 cells in vitro, but the ability of memory Th2 cells to produce Th2 cytokines was dramatically decreased. Histone methylation and acetylation at Th2 cytokine gene loci was not maintained in Mll +/- memory Th2 cells. Levels of Gata3 (131320) mRNA were normal in Mll +/- effector Th2 cells, but they were substantially decreased in Mll +/- memory Th2 cells; mRNA levels of other transcription factors were not affected in Mll +/- memory Th2 cells. Histone modifications of Gata3 were also aberrant in Th2 cell lines in which Mll expression had been knocked down by small interfering RNA. Ovalbumin-induced allergic eosinophilic inflammation was reduced in Mll +/- Th2 cell-transferred mice. Yamashita et al. (2006) concluded that MLL plays a crucial role in control of memory Th2 cell responses by maintaining expression of GATA3 and production of Th2 cytokines. </p><p>Barabe et al. (2007) demonstrated that upon transplantation into immunodeficient mice, primitive human hematopoietic cells expressing a mixed-lineage leukemia (MLL) fusion gene generated myeloid or lymphoid acute leukemias, with features that recapitulated human diseases. Analysis of serially transplanted mice revealed that the disease is sustained by leukemia-initiating cells that have evolved over time from a primitive cell type with a germline immunoglobulin heavy chain (IgH) gene configuration to a cell type containing rearranged IgH genes. The leukemia-initiating cells retained both myeloid and lymphoid lineage potential and remained responsive to microenvironmental cues. Barabe et al. (2007) concluded that the properties of these cells provide a biologic basis for several clinical hallmarks of MLL leukemias. </p><p>McMahon et al. (2007) found that fetal liver from Mll-knockout mouse embryos showed defects in the hematopoietic stem and progenitor pool, including reductions in long-term and short-term hematopoietic stem cell numbers and a decrease in the quiescent hematopoietic stem cell fraction. Adult mice with conditional Mll knockout had no apparent abnormalities in mature hematopoietic cells in bone marrow, spleen, and thymus. However, conditional Mll-knockout bone marrow cells produced reduced numbers of colony-forming units and showed reduced ability to compete in hematopoietic reconstitution assays. McMahon et al. (2007) concluded that MLL has a critical role in regulating stem cell self-renewal. </p>
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</span>
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<div>
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<br />
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</div>
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</div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>ALLELIC VARIANTS</strong>
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</span>
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<strong>8 Selected Examples):</strong>
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</span>
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</h4>
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<div>
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<p />
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0001 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KMT2A, 4-BP DEL, NT8806
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<br />
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SNP: rs398122878,
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ClinVar: RCV000030721, RCV003556091
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In a 6-year-old boy (WSS-1) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 4-bp deletion (8806_8809del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Val2936Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
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<strong>.0002 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KMT2A, 1-BP DEL, NT8267
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<br />
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SNP: rs398122879,
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ClinVar: RCV000030722
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</span>
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</div>
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<div>
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<span class="mim-text-font">
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<p>In an 8-year-old girl (WSS-2) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp deletion (8267del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Leu2756Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. </p>
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
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<span class="mim-font">
|
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<strong>.0003 WIEDEMANN-STEINER SYNDROME</strong>
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KMT2A, 1-BP DEL, NT6913
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<br />
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SNP: rs398122880,
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ClinVar: RCV000030723
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</span>
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</div>
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<div>
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<span class="mim-text-font">
|
|
<p>In a 12-year-old girl (WSS-3) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp deletion (6913del) in exon 27 of the MLL gene, predicted to cause a frameshift and premature termination (Ser2305LeufsTer2). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. The level of MLL transcript in patient skin fibroblasts was reduced in comparison to unrelated healthy controls, indicating nonsense-mediated decay. </p>
|
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</span>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<div>
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<h4>
|
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<span class="mim-font">
|
|
<strong>.0004 WIEDEMANN-STEINER SYNDROME</strong>
|
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</span>
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</h4>
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</div>
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<div>
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<span class="mim-text-font">
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KMT2A, ARG2382TER
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<br />
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SNP: rs387907275,
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ClinVar: RCV000030724
|
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</span>
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</div>
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<div>
|
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<span class="mim-text-font">
|
|
<p>In an 8-year-old boy (WSS-5) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 7144C-T transition in exon 27 of the MLL gene, resulting in an arg2382-to-ter (R2382X) substitution. The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. </p>
|
|
</span>
|
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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|
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<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0005 WIEDEMANN-STEINER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
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|
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|
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<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2A, 1-BP DUP, NT4599
|
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|
|
|
<br />
|
|
|
|
SNP: rs398122881,
|
|
|
|
|
|
|
|
ClinVar: RCV000030725
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 24-year-old woman (WSS-6) with Wiedemann-Steiner syndrome (WDSTS; 605130), Jones et al. (2012) identified heterozygosity for a de novo 1-bp duplication (4599dup) in the MLL gene, predicted to cause a frameshift and premature termination (Lys1534Ter). The mutation was not found in the unaffected parents, in the dbSNP or 1000 Genomes Project databases, or in 600 unrelated control exome profiles. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0006 WIEDEMANN-STEINER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2A, ARG2480TER
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555046568,
|
|
|
|
|
|
|
|
ClinVar: RCV000520124, RCV000626313, RCV004639263
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old Japanese boy (patient 1) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous c.7438C-T transition (c.7438C-T, NM_001197104.1) in the KMT2A gene, resulting in an arg2480-to-ter (R2480X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0007 WIEDEMANN-STEINER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2A, CYS1189TYR
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555038125,
|
|
|
|
|
|
|
|
ClinVar: RCV000626314
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 4-year-old Australian boy (patient 3) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous c.3566G-A transition (c.3566G-A, NM_001197104.1) in the KMT2A gene, resulting in a cys1189-to-tyr (C1189Y) substitution at a highly conserved residue in the CXXC zinc finger domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
<div>
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>.0008 WIEDEMANN-STEINER SYNDROME</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
|
|
KMT2A, 1-BP DEL, 1038A
|
|
|
|
|
|
<br />
|
|
|
|
SNP: rs1555035779,
|
|
|
|
|
|
|
|
ClinVar: RCV000626315
|
|
|
|
|
|
</span>
|
|
</div>
|
|
|
|
|
|
<div>
|
|
<span class="mim-text-font">
|
|
<p>In a 3-year-old Japanese girl (patient 5) with Wiedemann-Steiner syndrome (WDSTS; 605130), Miyake et al. (2016) identified a de novo heterozygous 1-bp deletion (c.1038delA, NM_001197104.1) in the KMT2A gene, predicted to result in a frameshift and premature termination (Val347LeufsTer53) in the N-terminal region of the protein. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the dbSNP (build 137/138), Exome Variant Server, 1000 Genomes Project, or in 575 in-house control exomes. Functional studies of the variant and studies of patient cells were not performed. </p>
|
|
</span>
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
</div>
|
|
|
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|
|
|
</div>
|
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|
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|
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|
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|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Armstrong, S. A., Staunton, J. E., Silverman, L. B., Pieters, R., den Boer, M. L., Minden, M. D., Sallan, S. E., Lander, E. S., Golub, T. R., Korsmeyer, S. J.
|
|
<strong>MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.</strong>
|
|
Nature Genet. 30: 41-47, 2002.
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|
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|
|
[PubMed: 11731795]
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|
|
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|
|
[Full Text: https://doi.org/10.1038/ng765]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
|
Baffa, R., Negrini, M., Schichman, S. A., Huebner, K., Croce, C. M.
|
|
<strong>Involvement of the ALL-1 gene in a solid tumor.</strong>
|
|
Proc. Nat. Acad. Sci. 92: 4922-4926, 1995.
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|
|
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|
|
[PubMed: 7761425]
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|
|
[Full Text: https://doi.org/10.1073/pnas.92.11.4922]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Barabe, F., Kennedy, J. A., Hope, K. J., Dick, J. E.
|
|
<strong>Modeling the initiation and progression of human acute leukemia in mice.</strong>
|
|
Science 316: 600-604, 2007.
|
|
|
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|
|
[PubMed: 17463288]
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|
|
[Full Text: https://doi.org/10.1126/science.1139851]
|
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</p>
|
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</li>
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Borkhardt, A., Bojesen, S., Haas, O. A., Fuchs, U., Bartelheimer, D., Loncarevic, I. F., Bohle, R. M., Harbott, J., Repp, R., Jaeger, U., Viehmann, S., Henn, T., Korth, P., Scharr, D., Lampert, F.
|
|
<strong>The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q.</strong>
|
|
Proc. Nat. Acad. Sci. 97: 9168-9173, 2000.
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|
|
|
|
|
[PubMed: 10908648]
|
|
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|
|
[Full Text: https://doi.org/10.1073/pnas.150079597]
|
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</p>
|
|
</li>
|
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|
|
<li>
|
|
<p class="mim-text-font">
|
|
Brightman, D. S., Grant, R. L., Ruzycki, P. A., Suzuki, R., Henning, A. K., Chen, S.
|
|
<strong>MLL1 is essential for retinal neurogenesis and horizontal inner neuron integrity.</strong>
|
|
Sci. Rep. 8: 11902, 2018. Note: Electronic Article.
|
|
|
|
|
|
[PubMed: 30093671]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/s41598-018-30355-3]
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Bruch, J., Wilda, M., Teigler-Schlegel, A., Harbott, J., Borkhardt, A., Metzler, M.
|
|
<strong>Occurrence of an MLL/LAF4 fusion gene caused by the insertion ins(11;2)(q23;q11.2q11.2) in an infant with acute lymphoblastic leukemia. (Letter)</strong>
|
|
Genes Chromosomes Cancer 37: 106-109, 2003.
|
|
|
|
|
|
[PubMed: 12661012]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1002/gcc.10187]
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Butler, L. H., Slany, R., Cui, X., Cleary, M. L., Mason, D. Y.
|
|
<strong>The HRX proto-oncogene product is widely expressed in human tissues and localizes to nuclear structures.</strong>
|
|
Blood 89: 3361-3370, 1997.
|
|
|
|
|
|
[PubMed: 9129043]
|
|
|
|
|
|
|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Caligiuri, M. A., Strout, M. P., Oberkircher, A. R., Yu, F., de la Chapelle, A., Bloomfield, C. D.
|
|
<strong>The partial tandem duplication of ALL1 in acute myeloid leukemia with normal cytogenetics or trisomy 11 is restricted to one chromosome.</strong>
|
|
Proc. Nat. Acad. Sci. 94: 3899-3902, 1997.
|
|
|
|
|
|
[PubMed: 9108076]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1073/pnas.94.8.3899]
|
|
|
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Chinwalla, V., Chien, A., Odero, M., Neilly, M. B., Zeleznik-Le, N. J., Rowley, J. D.
|
|
<strong>A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15.</strong>
|
|
Oncogene 22: 1400-1410, 2003.
|
|
|
|
|
|
[PubMed: 12618766]
|
|
|
|
|
|
[Full Text: https://doi.org/10.1038/sj.onc.1206273]
|
|
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|
|
</p>
|
|
</li>
|
|
|
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[Full Text: https://doi.org/10.1073/pnas.88.23.10735]
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Bao Lige - updated : 04/25/2024<br>Bao Lige - updated : 11/23/2021<br>Ada Hamosh - updated : 09/08/2020<br>Bao Lige - updated : 02/07/2019<br>Cassandra L. Kniffin - updated : 04/24/2018<br>Ada Hamosh - updated : 12/19/2016<br>Ada Hamosh - updated : 11/24/2015<br>Marla J. F. O'Neill - updated : 9/11/2012<br>Patricia A. Hartz - updated : 3/23/2012<br>Ada Hamosh - updated : 3/13/2012<br>Patricia A. Hartz - updated : 8/31/2011<br>Ada Hamosh - updated : 9/29/2010<br>Ada Hamosh - updated : 4/15/2010<br>Ada Hamosh - updated : 4/28/2009<br>Ada Hamosh - updated : 12/30/2008<br>Matthew B. Gross - updated : 10/13/2008<br>Matthew B. Gross - reorganized : 10/13/2008<br>Patricia A. Hartz - updated : 5/2/2008<br>Ada Hamosh - updated : 3/19/2008<br>Paul J. Converse - updated : 10/30/2007<br>Patricia A. Hartz - updated : 8/10/2007<br>Ada Hamosh - updated : 6/4/2007<br>Paul J. Converse - updated : 1/8/2007<br>Patricia A. Hartz - updated : 4/13/2006<br>Patricia A. Hartz - updated : 2/8/2006<br>Patricia A. Hartz - updated : 1/28/2005<br>Patricia A. Hartz - updated : 8/26/2004<br>Stylianos E. Antonarakis - updated : 11/19/2003<br>Stylianos E. Antonarakis - updated : 4/29/2003<br>Jane Kelly - updated : 3/10/2003<br>Victor A. McKusick - updated : 10/14/2002<br>Victor A. McKusick - updated : 2/20/2002<br>Victor A. McKusick - updated : 1/14/2002<br>Victor A. McKusick - updated : 11/13/2001<br>Victor A. McKusick - updated : 8/17/2001<br>Victor A. McKusick - updated : 4/2/2001<br>George E. Tiller - updated : 9/18/2000<br>Victor A. McKusick - updated : 7/19/2000<br>Wilson H. Y. Lo - updated : 9/22/1999<br>Wilson H. Y. Lo - updated : 7/23/1999<br>Victor A. McKusick - updated : 9/3/1997<br>Victor A. McKusick - updated : 6/18/1997
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Victor A. McKusick : 1/27/1992
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