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<title>
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Entry
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- #607785 - JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
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- OMIM
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#description">Description</a>
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<a href="#clinicalFeatures">Clinical Features</a>
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<a href="#cytogenetics">Cytogenetics</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#genotypePhenotypeCorrelations">Genotype/Phenotype Correlations</a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=86834" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<div><a href="https://www.alliancegenome.org/disease/DOID:0050458" 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="http://www.informatics.jax.org/disease/607785" class="mim-tip-hint" title="Phenotypes, alleles, and disease models from Mouse Genome Informatics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Phenotype', 'domain': 'informatics.jax.org'})">MGI Mouse Phenotype</a></div>
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<div><a href="https://omia.org/OMIA002299/" class="mim-tip-hint" title="Online Mendelian Inheritance in Animals (OMIA) is a database of genes, inherited disorders and traits in 191 animal species (other than human and mouse.)" target="_blank">OMIA</a></div>
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<div><a href="https://wormbase.org/resources/disease/DOID:0050458" class="mim-tip-hint" title="Database of the biology and genome of Caenorhabditis elegans and related nematodes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Wormbase Disease Ontology', 'domain': 'wormbase.org'})">Wormbase Disease Ontology</a></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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<a id="title" class="mim-anchor"></a>
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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> 127225006, 128831004, 128832006, 277587001, 445227008<br />
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<strong>ICD10CM:</strong> C93.1, C93.10, C93.3, C93.30<br />
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<strong>ORPHA:</strong> 86834<br />
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<strong>DO:</strong> 0050458<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="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
|
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607785
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</span>
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</span>
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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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JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
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</span>
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</h3>
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</div>
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<div>
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<br />
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<a id="alternativeTitles" class="mim-anchor"></a>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
|
|
</span>
|
|
</p>
|
|
</div>
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
LEUKEMIA, JUVENILE MYELOMONOCYTIC
|
|
</span>
|
|
</h4>
|
|
</div>
|
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</div>
|
|
<div>
|
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<br />
|
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</div>
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<div>
|
|
<a id="includedTitles" class="mim-anchor"></a>
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<div>
|
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<p>
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<span class="mim-font">
|
|
Other entities represented in this entry:
|
|
</span>
|
|
</p>
|
|
</div>
|
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<div>
|
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<span class="h3 mim-font">
|
|
LEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, INCLUDED
|
|
</span>
|
|
</div>
|
|
|
|
</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>
|
|
<a id="phenotypeMap" class="mim-anchor"></a>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Phenotype-Gene Relationships</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<table class="table table-bordered table-condensed table-hover small mim-table-padding">
|
|
<thead>
|
|
<tr class="active">
|
|
<th>
|
|
Location
|
|
</th>
|
|
<th>
|
|
Phenotype
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> MIM number
|
|
</th>
|
|
<th>
|
|
Inheritance
|
|
</th>
|
|
<th>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/5/619?start=-3&limit=10&highlight=619">
|
|
5q31.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607785"> 607785 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
ARHGAP26
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/605370"> 605370 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/11/1012?start=-3&limit=10&highlight=1012">
|
|
11q23.3
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
?Juvenile myelomonocytic leukemia
|
|
|
|
<span class="mim-tip-hint" title="A question mark (?) indicates that the relationship between the phenotype and gene is provisional">
|
|
<span class="glyphicon glyphicon-question-sign" aria-hidden="true"></span>
|
|
</span>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607785"> 607785 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CBL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/165360"> 165360 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/12/823?start=-3&limit=10&highlight=823">
|
|
12q24.13
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic, somatic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607785"> 607785 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PTPN11
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/176876"> 176876 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/geneMap/17/380?start=-3&limit=10&highlight=380">
|
|
17q11.2
|
|
</a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/607785"> 607785 </a>
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>, <abbr class="mim-tip-hint" title="Somatic mutation">SMu</abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
NF1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
<a href="/entry/613113"> 613113 </a>
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
|
|
|
|
<div class="btn-group ">
|
|
<a href="/clinicalSynopsis/607785" class="btn btn-warning" role="button"> Clinical Synopsis </a>
|
|
<button type="button" id="mimPhenotypicSeriesToggle" class="btn btn-warning dropdown-toggle mimSingletonFoldToggle" data-toggle="collapse" href="#mimClinicalSynopsisFold" onclick="ga('send', 'event', 'Unfurl', 'ClinicalSynopsis', 'omim.org')">
|
|
<span class="caret"></span>
|
|
<span class="sr-only">Toggle Dropdown</span>
|
|
</button>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div class="btn-group">
|
|
<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
|
PheneGene Graphics <span class="caret"></span>
|
|
</button>
|
|
<ul class="dropdown-menu" style="width: 17em;">
|
|
<li><a href="/graph/linear/607785" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/607785" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
|
</ul>
|
|
</div>
|
|
<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>
|
|
|
|
|
|
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
|
|
<div id="mimClinicalSynopsisFold" class="well well-sm collapse mimSingletonToggleFold">
|
|
<div class="small" style="margin: 5px">
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> INHERITANCE </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Autosomal dominant <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/263681008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">263681008</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/771269000" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">771269000</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0443147&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0443147</a>, <a href="https://bioportal.bioontology.org/search?q=C1867440&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1867440</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0000006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0000006</a>]</span><br /> -
|
|
Somatic mutation <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/124975008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">124975008</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C1866227&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C1866227</a>, <a href="https://bioportal.bioontology.org/search?q=C0544886&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0544886</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0001442" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0001442</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
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|
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|
|
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|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> HEMATOLOGY </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Juvenile myelomonocytic leukemia <span class="mim-feature-ids hidden">[SNOMEDCT: <a href="https://purl.bioontology.org/ontology/SNOMEDCT/128832006" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">128832006</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/277587001" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">277587001</a>, <a href="https://purl.bioontology.org/ontology/SNOMEDCT/445227008" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'SNOMEDCT\', \'domain\': \'bioontology.org\'})">445227008</a>]</span> <span class="mim-feature-ids hidden">[ICD10CM: <a href="https://purl.bioontology.org/ontology/ICD10CM/C93.30" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C93.30</a>, <a href="https://purl.bioontology.org/ontology/ICD10CM/C93.3" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'ICD10CM\', \'domain\': \'bioontology.org\'})">C93.3</a>]</span> <span class="mim-feature-ids hidden">[UMLS: <a href="https://bioportal.bioontology.org/search?q=C0349639&searchproperties=true" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'UMLS\', \'domain\': \'bioontology.org\'})">C0349639</a> HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012209</a>]</span> <span class="mim-feature-ids hidden">[HPO: <a href="https://hpo.jax.org/app/browse/term/HP:0012209" target="_blank" onclick="gtag(\'event\', \'mim_outbound\', {\'name\': \'HPO\', \'domain\': \'hpo.jax.org\'})">HP:0012209</a>]</span><br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
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<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MISCELLANEOUS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- One family has been reported with germline CBL mutation (last curated May 2016)<br />
|
|
|
|
</span>
|
|
</div>
|
|
|
|
</div>
|
|
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<div>
|
|
<span class="h5 mim-font">
|
|
<strong> MOLECULAR BASIS </strong>
|
|
</span>
|
|
</div>
|
|
<div style="margin-left: 2em;">
|
|
|
|
<div>
|
|
<span class="mim-font">
|
|
|
|
- Caused by mutation in the CBL gene (CBL, <a href="/entry/165360#0009">165360.0009</a>)<br /> -
|
|
Caused by mutation in the NF1 gene (NF1, <a href="/entry/613113#0019">613113.0019</a>)<br /> -
|
|
Caused by somatic mutation in the RHO GTPase-activating protein 26 gene (ARHGAP26, <a href="/entry/605370#0001">605370.0001</a>)<br /> -
|
|
Caused by somatic mutation in the protein tyrosine phosphatase, nonreceptor-type, 11 gene (PTPN11, <a href="/entry/176876#0014">176876.0014</a>)<br /> -
|
|
Caused by somatic mutation in the neuroblastoma Ras viral oncogene (NRAS, <a href="/entry/164790#0003">164790.0003</a>)<br /> -
|
|
Caused by somatic mutation in the Kirsten rat sarcoma-2 viral (v-Ki-ras2) oncogene homolog gene (KRAS, <a href="/entry/190070#0003">190070.0003</a>)<br />
|
|
|
|
</span>
|
|
</div>
|
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</div>
|
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|
|
</div>
|
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|
|
<div class="text-right">
|
|
<a href="#mimClinicalSynopsisFold" data-toggle="collapse">▲ Close</a>
|
|
</div>
|
|
</div>
|
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</div>
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</div>
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<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
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|
|
<div>
|
|
<a id="text" class="mim-anchor"></a>
|
|
|
|
|
|
|
|
<h4 href="#mimTextFold" id="mimTextToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
|
<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
|
|
|
<span class="mim-font">
|
|
<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.">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</span>
|
|
</h4>
|
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<p>A number sign (#) is used with this entry because of evidence that juvenile myelomonocytic leukemia (JMML) can be caused by germline heterozygous mutation in the CBL gene (<a href="/entry/165360">165360</a>) on chromosome 11q23. One such family has been reported.</p>
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<p>Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (<a href="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al., 2009</a>). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (<a href="#5" class="mim-tip-reference" title="Hasle, H., Arico, M., Basso, G., Biondi, A., Rajnoldi, A. C., Creutzig, U., Fenu, S., Fonatsch, C., Haas, O. A., Harbott, J., Kardos, G., Kerndrup, G., and 11 others. <strong>Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7.</strong> Leukemia 13: 376-385, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086728</a>] [<a href="https://doi.org/10.1038/sj.leu.2401342" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10086728">Hasle et al., 1999</a>). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (<a href="#13" class="mim-tip-reference" title="Niemeyer, C. M., Arico, M., Basso, G., Biondi, A., Cantu Rajnoldi, A., Creutzig, U., Haas, O., Harbott, J., Hasle, H., Kerndrup, G., Locatelli, F., Mann, G., Stollmann-Gibbels, B., van't Veer-Korthof, E. T., van Wering, E., Zimmermann, M., European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). <strong>Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases.</strong> Blood 89: 3534-3543, 1997.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9160658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9160658</a>]" pmid="9160658">Niemeyer et al., 1997</a>). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (<a href="/entry/601511">601511</a>) hyperphosphorylation (<a href="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al., 2009</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=9160658+10086728+19571318" 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>Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia</em></strong></p><p>
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In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (<a href="/entry/176876">176876</a>), KRAS (<a href="/entry/190070">190070</a>), and NRAS (<a href="/entry/164790">164790</a>) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (<a href="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al., 2009</a>). Somatic disruptions of the GRAF gene (ARHGAP26; <a href="/entry/605370">605370</a>) have also been found in patients with JMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19571318" 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>About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; <a href="/entry/162200">162200</a>) due to germline mutations in the NF1 gene (<a href="/entry/613113">613113</a>). In addition, patients with Noonan syndrome (NS1, <a href="/entry/163950">163950</a>; NS3, <a href="/entry/609942">609942</a>) or Noonan syndrome-like disorder (NSLL; <a href="/entry/613563">613563</a>) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML.</p><p><strong><em>Genetic Heterogeneity of Chronic Myelomonocytic Leukemia</em></strong></p><p>
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Somatic mutations in the CBL, ASXL1 (<a href="/entry/612990">612990</a>), TET2 (<a href="/entry/612839">612839</a>), and SF3B1 (<a href="/entry/605590">605590</a>) genes have been found in patients with CMML.</p>
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<p><a href="#14" class="mim-tip-reference" title="Pathak, A., Pemov, A., McMaster, M. L., Dewan, R., Ravichandran, S., Pak, E., Dutra, A., Lee, H. J., Vogt, A., Zhang, X., Yeager, M., Anderson, S., Kirby, M., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Caporaso, N., Greene, M. H., Goldin, L. R., Stewart, D. R. <strong>Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family.</strong> Hum. Genet. 134: 775-787, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939664</a>] [<a href="https://doi.org/10.1007/s00439-015-1550-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25939664">Pathak et al. (2015)</a> reported a family in which 4 patients developed leukemia in the first few years of life. One patient died at age 16 months, whereas the other 3 patients were followed for 35 years. Retrospective diagnosis was consistent with JMML. Two of the patients had some persistent hematologic abnormalities into adulthood, and the third had continued splenomegaly. None had clinical features consistent with Noonan syndrome (see <a href="/entry/613563">613563</a>), although 1 of the patients had dysmorphic facial features at age 18 months, including slanted palpebral fissures, small mouth, long grooved philtrum, short upturned nose, and facial hypotonia. Several other family members had acute myelomonocytic leukemia, splenomegaly, polyclonal gammopathy, and monocytosis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939664" 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>In a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation, <a href="#16" class="mim-tip-reference" title="Ross, T. S., Bernard, O. A., Berger, R., Gilliland, D. G. <strong>Fusion of huntingtin interacting protein 1 to platelet-derived growth factor-beta receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).</strong> Blood 91: 4419-4426, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616134</a>]" pmid="9616134">Ross et al. (1998)</a> found fusion of the HIP1 gene (<a href="/entry/601767">601767</a>) to the platelet-derived growth factor-beta receptor gene (PDGFRB; <a href="/entry/173410">173410</a>). They identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFRB gene. The reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein product was a 180-kD protein when expressed in a murine hematopoietic cell line and was constitutively tyrosine phosphorylated. Furthermore, the fusion gene transformed the same mouse hematopoietic cell line to interleukin-3-independent growth. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9616134" 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 a patient with CMML and an acquired t(5;17)(q33;p13), <a href="#10" class="mim-tip-reference" title="Magnusson, M. K., Meade, K. E., Brown, K. E., Arthur, D. C., Krueger, L. A., Barrett, A. J., Dunbar, C. E. <strong>Rabaptin-5 is a novel fusion partner to platelet-derived growth factor beta receptor in chronic myelomonocytic leukemia.</strong> Blood 98: 2518-2525, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11588050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11588050</a>] [<a href="https://doi.org/10.1182/blood.v98.8.2518" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11588050">Magnusson et al. (2001)</a> demonstrated rabaptin-5 (RABEP1; <a href="/entry/603616">603616</a>) as a novel partner fused in-frame to the 5-prime portion of the PDGFBR gene. The fusion protein included more than 85% of the native rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRB. Rabaptin-5 is an essential and rate-limiting component of early endosomal fusion. The new fusion protein links 2 important pathways of growth regulation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11588050" 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="#19" class="mim-tip-reference" title="Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D. <strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong> Nature Genet. 34: 148-150, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>] [<a href="https://doi.org/10.1038/ng1156" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12717436">Tartaglia et al. (2003)</a> showed that germline mutations in PTPN11 lead to Noonan syndrome-1 (NS1; <a href="/entry/163950">163950</a>) associated with JMML (T73I; <a href="/entry/176876#0011">176876.0011</a>), and that somatic mutations in PTPN11 are associated with isolated JMML. <a href="#7" class="mim-tip-reference" title="Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I. <strong>Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature.</strong> Am. J. Med. Genet. 134A: 165-170, 2005.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15723289/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15723289</a>] [<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15723289">Jongmans et al. (2005)</a> described a patient with Noonan syndrome and mild JMML who carried a mutation in the PTPN11 gene (<a href="/entry/176876#0011">176876.0011</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=12717436+15723289" 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="#18" class="mim-tip-reference" title="Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P. <strong>Germline KRAS mutations cause Noonan syndrome.</strong> Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>] [<a href="https://doi.org/10.1038/ng1748" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16474405">Schubbert et al. (2006)</a> described a 3-month-old female with Noonan syndrome-3 (NS3; <a href="/entry/609942">609942</a>) and a severe clinical phenotype who presented with a JMML-like myeloproliferative disorder. The patient was heterozygous for a mutation in the KRAS gene (T58I; <a href="/entry/190070#0011">190070.0011</a>). This mutation was also present in her buccal cells, but was absent in parental DNA. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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="#2" class="mim-tip-reference" title="De Filippi, P., Zecca, M., Lisini, D., Rosti, V., Cagioni, C., Carlo-Stella, C., Radi, O., Veggiotti, P., Mastronuzzi, A., Acquaviva, A., D'Ambrosio, A., Locatelli, F., Danesino, C. <strong>Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia.</strong> Brit. J. Haemat. 147: 706-709, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19775298/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19775298</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2009.07894.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19775298">De Filippi et al. (2009)</a> reported a boy who presented in infancy with JMML but was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome (NS6; <a href="/entry/613224">613224</a>). Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. Genetic analysis revealed a de novo germline heterozygous mutation in the NRAS gene (G13D; <a href="/entry/164790#0003">164790.0003</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19775298" 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 3 unrelated patients with a Noonan syndrome-like disorder (<a href="/entry/613563">613563</a>) who developed JMML, <a href="#15" class="mim-tip-reference" title="Perez, B., Mechinaud, F., Galambrun, C., Ben Romdhane, N., Isidor, B., Philip, N., Derain-Court, J., Cassinat, B., Lachenaud, J., Kaltenbach, S., Salmon, A., Desiree, C., Pereira, S., Menot, M. L., Royer, N., Fenneteau, O., Baruchel, A., Chomienne, C., Verloes, A., Cave, H. <strong>Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.</strong> J. Med. Genet. 47: 686-691, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20543203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20543203</a>] [<a href="https://doi.org/10.1136/jmg.2010.076836" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20543203">Perez et al. (2010)</a> identified a heterozygous germline mutation in the CBL gene (Y371H; <a href="/entry/165360#0005">165360.0005</a>). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that germline heterozygous mutations in the CBL gene are associated with predisposition for the development of JMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20543203" 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 27 of 159 leukemia samples from patients with JMML, <a href="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al. (2009)</a> identified 25 homozygous and 2 heterozygous mutations in the CBL gene. The mutations were located throughout the linker and RING finger domains, and Y371H was the most common mutation. Leukemic cells from 3 patients examined in detail had acquired isodisomy of chromosome 11q including the CBL gene. Each of these 3 patients had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (<a href="/entry/601511">601511</a>) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. <a href="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al. (2009)</a> estimated the frequency of CBL mutations to be 10 to 15% of JMML patients overall. They did not find CBL mutations in JMML patients with known PTPN11/RAS mutation, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19571318" 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>Isolated Juvenile or Chronic Myelomonocytic Leukemia</em></strong></p><p>
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In 3 affected members of a family with JMML, <a href="#14" class="mim-tip-reference" title="Pathak, A., Pemov, A., McMaster, M. L., Dewan, R., Ravichandran, S., Pak, E., Dutra, A., Lee, H. J., Vogt, A., Zhang, X., Yeager, M., Anderson, S., Kirby, M., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Caporaso, N., Greene, M. H., Goldin, L. R., Stewart, D. R. <strong>Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family.</strong> Hum. Genet. 134: 775-787, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939664</a>] [<a href="https://doi.org/10.1007/s00439-015-1550-9" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25939664">Pathak et al. (2015)</a> identified a germline heterozygous missense mutation in the CBL gene (Y371C; <a href="/entry/165360#0009">165360.0009</a>). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in 4 family members without JMML, consistent with incomplete penetrance. Structural modeling predicted that the mutation would abrogate the ability of the mutant protein to adopt a conformation that would permit protein ubiquitination. Functional studies of the variant were not performed. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939664" 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 white blood cells derived from 11 patients with juvenile myelomonocytic leukemia, <a href="#11" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, <a href="/entry/190070#0003">190070.0003</a>; G12D, <a href="/entry/190070#0005">190070.0005</a>; and G12S, <a href="/entry/190070#0007">190070.0007</a>) and 5 different somatic mutations in the NRAS gene (see, e.g., G12D, <a href="/entry/164790#0007">164790.0007</a> and G13D, <a href="/entry/164790#0003">164790.0003</a>). Each patient carried a single somatic mutation. The patients were ascertained from a cohort of 80 children with JMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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="#6" class="mim-tip-reference" title="Jankowska, A. M., Szpurka, H., Tiu, R. V., Makishima, H., Afable, M., Huh, J., O'Keefe, C. L., Ganetzky, R., McDevitt, M. A., Maciejewski, J. P. <strong>Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms.</strong> Blood 113: 6403-6410, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19372255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19372255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19372255[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/10.1182/blood-2009-02-205690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19372255">Jankowska et al. (2009)</a> identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in patients with MDS/MPD. Subsequent analysis identified somatic mutations in the TET2 gene (<a href="/entry/612839">612839</a>) in 6 of 17 cases of chronic myelomonocytic leukemia. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19372255" 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="#1" class="mim-tip-reference" title="Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., Huberman, K., Thomas, S., and 12 others. <strong>Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies.</strong> Blood 114: 144-147, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19420352/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19420352</a>] [<a href="https://doi.org/10.1182/blood-2009-03-210039" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19420352">Abdel-Wahab et al. (2009)</a> identified somatic mutations in the TET2 gene in 29 (42%) of 69 CMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19420352" 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="#4" class="mim-tip-reference" title="Gelsi-Boyer, V., Trouplin, V., Adelaide, J., Bonansea, J., Cervera, N., Carbuccia, N., Lagarde, A., Prebet, T., Nezri, M., Sainty, D., Olschwang, S., Xerri, L., Chaffanet, M., Mozziconacci, M.-J., Vey, N., Birnbaum, D. <strong>Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.</strong> Brit. J. Haemat. 145: 788-800, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19388938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19388938</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2009.07697.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19388938">Gelsi-Boyer et al. (2009)</a> presented evidence that the ASXL1 gene (<a href="/entry/612990">612990</a>) may act as a tumor suppressor in myeloid malignancies. They identified somatic ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic leukemia samples. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19388938" 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="#9" class="mim-tip-reference" title="Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others. <strong>Mutations in CBL occur frequently in juvenile myelomonocytic leukemia.</strong> Blood 114: 1859-1863, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>] [<a href="https://doi.org/10.1182/blood-2009-01-198416" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19571318">Loh et al. (2009)</a> found isolated CBL mutations in 4 of 44 samples from patients with CMML, which shares features with JMML. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19571318" 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="#12" class="mim-tip-reference" title="Muramatsu, H., Makishima, H., Jankowska, A. M., Cazzolli, H., O'Keefe, C., Yoshida, N., Xu, Y., Nishio, N., Hama, A., Yagasaki, H., Takahashi, Y., Kato, K., Manabe, A., Kojima, S., Maciejewski, J. P. <strong>Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia.</strong> Blood 115: 1969-1975, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20008299[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/10.1182/blood-2009-06-226340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008299">Muramatsu et al. (2010)</a> identified uniparental disomy of 11q23 in leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the CBL gene identified somatic mutations in 5 (10%) of 49 patients. Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively. None of the patients had mutations in the TET2 gene (<a href="/entry/612839">612839</a>), which had previously been shown to be present in a significant proportion of patients with MDS/MPD, including CMML (see <a href="#6" class="mim-tip-reference" title="Jankowska, A. M., Szpurka, H., Tiu, R. V., Makishima, H., Afable, M., Huh, J., O'Keefe, C. L., Ganetzky, R., McDevitt, M. A., Maciejewski, J. P. <strong>Loss of heterozygosity 4q24 and TET2 mutations associated with myelodysplastic/myeloproliferative neoplasms.</strong> Blood 113: 6403-6410, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19372255/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19372255</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19372255[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/10.1182/blood-2009-02-205690" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19372255">Jankowska et al., 2009</a>). Eighteen (37%) of the 49 patients with JMML studied by <a href="#12" class="mim-tip-reference" title="Muramatsu, H., Makishima, H., Jankowska, A. M., Cazzolli, H., O'Keefe, C., Yoshida, N., Xu, Y., Nishio, N., Hama, A., Yagasaki, H., Takahashi, Y., Kato, K., Manabe, A., Kojima, S., Maciejewski, J. P. <strong>Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia.</strong> Blood 115: 1969-1975, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20008299[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/10.1182/blood-2009-06-226340" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20008299">Muramatsu et al. (2010)</a> did not have any of the known pathogenic defects. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=19372255+20008299" 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="#8" class="mim-tip-reference" title="Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I. <strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong> Nature 473: 230-233, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[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/nature09999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562564">Klinakis et al. (2011)</a> identified novel somatic-inactivating Notch (see <a href="/entry/190198">190198</a>) pathway mutations in a fraction of patients with CMML. Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (<a href="/entry/139605">139605</a>). <a href="#8" class="mim-tip-reference" title="Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I. <strong>A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.</strong> Nature 473: 230-233, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[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/nature09999" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21562564">Klinakis et al. (2011)</a> concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21562564" 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="#17" class="mim-tip-reference" title="Sakaguchi, H., Okuno, Y., Muramatsu, H., Yoshida, K., Shiraishi, Y., Takahashi, M., Kon, A., Sanada, M., Chiba, K., Tanaka, H., Makishima, H., Wang, X., and 10 others. <strong>Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia.</strong> Nature Genet. 45: 937-941, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23832011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23832011</a>] [<a href="https://doi.org/10.1038/ng.2698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23832011">Sakaguchi et al. (2013)</a> performed whole-exome sequencing for paired tumor-normal DNA from 13 individuals with JMML (cases), followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 nonsilent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 (<a href="/entry/611060">611060</a>) and JAK3 (<a href="/entry/600173">600173</a>) mutations were among common targets for secondary mutations. Mutations in JAK3 were often subclonal, and <a href="#17" class="mim-tip-reference" title="Sakaguchi, H., Okuno, Y., Muramatsu, H., Yoshida, K., Shiraishi, Y., Takahashi, M., Kon, A., Sanada, M., Chiba, K., Tanaka, H., Makishima, H., Wang, X., and 10 others. <strong>Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia.</strong> Nature Genet. 45: 937-941, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23832011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23832011</a>] [<a href="https://doi.org/10.1038/ng.2698" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23832011">Sakaguchi et al. (2013)</a> hypothesized that they may be involved in the progression rather than the initiation of leukemia; these mutations associated with poor clinical outcomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23832011" 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>Exclusion Studies</em></strong></p><p>
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<a href="#20" class="mim-tip-reference" title="Yoshida, N., Yagasaki, H., Takahashi, Y., Kudo, K., Manabe, A., Kojima, S. <strong>Mutation analysis of SIPA1 in patients with juvenile myelomonocytic leukemia. (Letter)</strong> Brit. J. Haemat. 142: 850-851, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18492118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18492118</a>] [<a href="https://doi.org/10.1111/j.1365-2141.2008.07249.x" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18492118">Yoshida et al. (2008)</a> excluded mutation in the SIPA1 gene (<a href="/entry/602180">602180</a>) as a cause of JMML in 16 specimens obtained from patients with the disorder who did not have mutations in the KRAS, NRAS, or PTPN11 genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18492118" 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="#11" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> reported 3 patients with an NRAS or KRAS gly12-to-ser (G12S) mutation who showed spontaneous improvement of hematologic abnormalities lasting for 2 to 4 years with neither intensive therapy nor HSCT. They suggested that the mild course correlated with the G12S RAS mutation and recommended that patients found to have this mutation receive close follow-up but no chemotherapy. <a href="#3" class="mim-tip-reference" title="Flotho, C., Kratz, C. P., Bergstrasser, E., Hasle, H., Stary, J., Trebo, M., van den Heuvel-Eibrink, M. M., Wojcik, D., Zecca, M., Locatelli, F., Niemeyer, C. M. <strong>Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. (Letter)</strong> Blood 111: 966-967, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18182584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18182584</a>] [<a href="https://doi.org/10.1182/blood-2007-09-111831" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18182584">Flotho et al. (2008)</a> viewed the recommendation of <a href="#11" class="mim-tip-reference" title="Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others. <strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong> Blood 109: 5477-5480, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>] [<a href="https://doi.org/10.1182/blood-2006-09-046649" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17332249">Matsuda et al. (2007)</a> as premature. They reviewed 50 patients with JMML who were not given HSCT within the first 3 years after diagnosis; of these, 17 survived without treatment from 4 to 21 years. Six of 7 carried a RAS mutation different from R12S. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18182584+17332249" 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://doi.org/10.1182/blood-2009-03-210039" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1111/j.1365-2141.2009.07894.x" target="_blank">Full Text</a>]
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<a id="Flotho2008" class="mim-anchor"></a>
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Flotho, C., Kratz, C. P., Bergstrasser, E., Hasle, H., Stary, J., Trebo, M., van den Heuvel-Eibrink, M. M., Wojcik, D., Zecca, M., Locatelli, F., Niemeyer, C. M.
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<strong>Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. (Letter)</strong>
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Blood 111: 966-967, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18182584/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18182584</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18182584" 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/10.1182/blood-2007-09-111831" target="_blank">Full Text</a>]
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<a id="Gelsi-Boyer2009" class="mim-anchor"></a>
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Gelsi-Boyer, V., Trouplin, V., Adelaide, J., Bonansea, J., Cervera, N., Carbuccia, N., Lagarde, A., Prebet, T., Nezri, M., Sainty, D., Olschwang, S., Xerri, L., Chaffanet, M., Mozziconacci, M.-J., Vey, N., Birnbaum, D.
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<strong>Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19388938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19388938</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19388938" 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/10.1111/j.1365-2141.2009.07697.x" target="_blank">Full Text</a>]
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<a id="5" class="mim-anchor"></a>
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<a id="Hasle1999" class="mim-anchor"></a>
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Hasle, H., Arico, M., Basso, G., Biondi, A., Rajnoldi, A. C., Creutzig, U., Fenu, S., Fonatsch, C., Haas, O. A., Harbott, J., Kardos, G., Kerndrup, G., and 11 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10086728/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10086728</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10086728" 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/sj.leu.2401342" target="_blank">Full Text</a>]
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<a id="Jankowska2009" class="mim-anchor"></a>
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Jankowska, A. M., Szpurka, H., Tiu, R. V., Makishima, H., Afable, M., Huh, J., O'Keefe, C. L., Ganetzky, R., McDevitt, M. A., Maciejewski, J. P.
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[<a href="https://doi.org/10.1182/blood-2009-02-205690" target="_blank">Full Text</a>]
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<a id="Jongmans2005" class="mim-anchor"></a>
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Jongmans, M., Sistermans, E. A., Rikken, A., Nillesen, W. M., Tamminga, R., Patton, M., Maier, E. M., Tartaglia, M., Noordam, K., van der Burgt, I.
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[<a href="https://doi.org/10.1002/ajmg.a.30598" target="_blank">Full Text</a>]
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<a id="Klinakis2011" class="mim-anchor"></a>
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Klinakis, A., Lobry, C., Abdel-Wahab, O., Oh, P., Haeno, H., Buonamici, S., van De Walle, I., Cathelin, S., Trimarchi, T., Araldi, E., Liu, C., Ibrahim, S., Beran, M., Zavadil, J., Efstratiadis, A., Taghon, T., Michor, F., Levine, R. L., Aifantis, I.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21562564/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21562564</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21562564[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=21562564" 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/nature09999" target="_blank">Full Text</a>]
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<a id="Loh2009" class="mim-anchor"></a>
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Loh, M. L., Sakai, D. S., Flotho, C., Kang, M., Fliegauf, M., Archambeault, S., Mullighan, C. G., Chen, L., Bergstraesser, E., Bueso-Ramos, C. E., Emanuel, P. D., Hasle, H., and 9 others.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19571318/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19571318</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19571318" 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/10.1182/blood-2009-01-198416" target="_blank">Full Text</a>]
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<a id="Magnusson2001" class="mim-anchor"></a>
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Magnusson, M. K., Meade, K. E., Brown, K. E., Arthur, D. C., Krueger, L. A., Barrett, A. J., Dunbar, C. E.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11588050/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11588050</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11588050" 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/10.1182/blood.v98.8.2518" target="_blank">Full Text</a>]
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<a id="Matsuda2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., Yanagimachi, M., Kikuchi, A., and 10 others.
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<strong>Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations.</strong>
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Blood 109: 5477-5480, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17332249/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17332249</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17332249" 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/10.1182/blood-2006-09-046649" target="_blank">Full Text</a>]
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<a id="Muramatsu2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Muramatsu, H., Makishima, H., Jankowska, A. M., Cazzolli, H., O'Keefe, C., Yoshida, N., Xu, Y., Nishio, N., Hama, A., Yagasaki, H., Takahashi, Y., Kato, K., Manabe, A., Kojima, S., Maciejewski, J. P.
|
|
<strong>Mutations of an E3 ubiquitin ligase c-Cbl but not TET2 mutations are pathogenic in juvenile myelomonocytic leukemia.</strong>
|
|
Blood 115: 1969-1975, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20008299/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20008299</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=20008299[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=20008299" 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/10.1182/blood-2009-06-226340" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="13" class="mim-anchor"></a>
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<a id="Niemeyer1997" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Niemeyer, C. M., Arico, M., Basso, G., Biondi, A., Cantu Rajnoldi, A., Creutzig, U., Haas, O., Harbott, J., Hasle, H., Kerndrup, G., Locatelli, F., Mann, G., Stollmann-Gibbels, B., van't Veer-Korthof, E. T., van Wering, E., Zimmermann, M., European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS).
|
|
<strong>Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases.</strong>
|
|
Blood 89: 3534-3543, 1997.
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|
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9160658/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9160658</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9160658" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="14" class="mim-anchor"></a>
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<a id="Pathak2015" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Pathak, A., Pemov, A., McMaster, M. L., Dewan, R., Ravichandran, S., Pak, E., Dutra, A., Lee, H. J., Vogt, A., Zhang, X., Yeager, M., Anderson, S., Kirby, M., NCI DCEG Cancer Genomics Research Laboratory, NCI DCEG Cancer Sequencing Working Group, Caporaso, N., Greene, M. H., Goldin, L. R., Stewart, D. R.
|
|
<strong>Juvenile myelomonocytic leukemia due to a germline CBL Y371C mutation: 35-year follow-up of a large family.</strong>
|
|
Hum. Genet. 134: 775-787, 2015.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25939664/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25939664</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25939664" 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/10.1007/s00439-015-1550-9" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="15" class="mim-anchor"></a>
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<a id="Perez2010" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Perez, B., Mechinaud, F., Galambrun, C., Ben Romdhane, N., Isidor, B., Philip, N., Derain-Court, J., Cassinat, B., Lachenaud, J., Kaltenbach, S., Salmon, A., Desiree, C., Pereira, S., Menot, M. L., Royer, N., Fenneteau, O., Baruchel, A., Chomienne, C., Verloes, A., Cave, H.
|
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<strong>Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia.</strong>
|
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J. Med. Genet. 47: 686-691, 2010.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20543203/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20543203</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20543203" 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/10.1136/jmg.2010.076836" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="16" class="mim-anchor"></a>
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<a id="Ross1998" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Ross, T. S., Bernard, O. A., Berger, R., Gilliland, D. G.
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<strong>Fusion of huntingtin interacting protein 1 to platelet-derived growth factor-beta receptor (PDGF-beta-R) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).</strong>
|
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Blood 91: 4419-4426, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9616134/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9616134</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9616134" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="17" class="mim-anchor"></a>
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<a id="Sakaguchi2013" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Sakaguchi, H., Okuno, Y., Muramatsu, H., Yoshida, K., Shiraishi, Y., Takahashi, M., Kon, A., Sanada, M., Chiba, K., Tanaka, H., Makishima, H., Wang, X., and 10 others.
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<strong>Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia.</strong>
|
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Nature Genet. 45: 937-941, 2013.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23832011/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23832011</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23832011" 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/ng.2698" target="_blank">Full Text</a>]
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</p>
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</div>
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<li>
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<a id="18" class="mim-anchor"></a>
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<a id="Schubbert2006" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Schubbert, S., Zenker, M., Rowe, S. L., Boll, S., Klein, C., Bollag, G., van der Burgt, I., Musante, L., Kalscheuer, V., Wehner, L.-E., Nguyen, H., West, B., Zhang, K. Y. J., Sistermans, E., Rauch, A., Niemeyer, C. M., Shannon, K., Kratz, C. P.
|
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<strong>Germline KRAS mutations cause Noonan syndrome.</strong>
|
|
Nature Genet. 38: 331-336, 2006. Note: Erratum: Nature Genet. 38: 598 only, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16474405/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16474405</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16474405" 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/ng1748" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="19" class="mim-anchor"></a>
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<a id="Tartaglia2003" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Tartaglia, M., Niemeyer, C. M., Fragale, A., Song, X., Buechner, J., Jung, A., Hahlen, K., Hasle, H., Licht, J. D., Gelb, B. D.
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<strong>Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.</strong>
|
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Nature Genet. 34: 148-150, 2003.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12717436/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12717436</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12717436" 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/ng1156" target="_blank">Full Text</a>]
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</p>
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</div>
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</li>
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<li>
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<a id="20" class="mim-anchor"></a>
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<a id="Yoshida2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Yoshida, N., Yagasaki, H., Takahashi, Y., Kudo, K., Manabe, A., Kojima, S.
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<strong>Mutation analysis of SIPA1 in patients with juvenile myelomonocytic leukemia. (Letter)</strong>
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Brit. J. Haemat. 142: 850-851, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18492118/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18492118</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18492118" 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/10.1111/j.1365-2141.2008.07249.x" target="_blank">Full Text</a>]
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</p>
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</ol>
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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="contributors" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="mim-text-font">
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<a href="#mimCollapseContributors" role="button" data-toggle="collapse"> Contributors: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 5/10/2016
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</span>
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</div>
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</div>
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<div class="row collapse" id="mimCollapseContributors">
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<div class="col-lg-offset-2 col-md-offset-4 col-sm-offset-4 col-xs-offset-2 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Ada Hamosh - updated : 1/28/2014<br>Cassandra L. Kniffin - updated : 8/1/2011<br>Cassandra L. Kniffin - updated : 5/25/2011<br>Ada Hamosh - updated : 5/23/2011<br>Cassandra L. Kniffin - updated : 5/3/2011<br>Carol A. Bocchini - updated : 6/1/2009<br>Cassandra L. Kniffin - updated : 3/9/2009<br>Victor A. McKusick - updated : 2/24/2006<br>Victor A. McKusick - updated : 4/14/2005
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</span>
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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="creationDate" class="mim-anchor"></a>
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<div class="row">
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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Creation Date:
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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Victor A. McKusick : 5/14/2003
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<a id="editHistory" class="mim-anchor"></a>
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<div class="col-lg-2 col-md-2 col-sm-4 col-xs-4">
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<span class="text-nowrap mim-text-font">
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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</span>
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</div>
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<div class="col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 02/16/2021
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</div>
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<div class="row collapse" id="mimCollapseEditHistory">
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<div class="col-lg-offset-2 col-md-offset-2 col-sm-offset-4 col-xs-offset-4 col-lg-6 col-md-6 col-sm-6 col-xs-6">
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<span class="mim-text-font">
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carol : 05/25/2016<br>carol : 5/13/2016<br>ckniffin : 5/10/2016<br>carol : 10/14/2015<br>alopez : 5/21/2015<br>carol : 11/18/2014<br>mcolton : 11/13/2014<br>ckniffin : 11/12/2014<br>carol : 4/18/2014<br>alopez : 1/28/2014<br>carol : 12/8/2011<br>carol : 11/29/2011<br>ckniffin : 10/24/2011<br>wwang : 8/9/2011<br>ckniffin : 8/1/2011<br>wwang : 6/2/2011<br>ckniffin : 5/31/2011<br>ckniffin : 5/31/2011<br>ckniffin : 5/25/2011<br>alopez : 5/24/2011<br>terry : 5/23/2011<br>wwang : 5/19/2011<br>ckniffin : 5/3/2011<br>ckniffin : 5/3/2011<br>carol : 11/23/2009<br>terry : 6/19/2009<br>terry : 6/1/2009<br>carol : 6/1/2009<br>wwang : 3/18/2009<br>ckniffin : 3/9/2009<br>carol : 7/31/2008<br>alopez : 3/3/2006<br>terry : 2/24/2006<br>tkritzer : 4/27/2005<br>terry : 4/14/2005<br>terry : 7/30/2003<br>alopez : 6/3/2003<br>alopez : 5/15/2003<br>alopez : 5/14/2003
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</span>
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<div>
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<div>
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<h3>
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<span class="mim-font">
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<strong>#</strong> 607785
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</span>
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</h3>
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</div>
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<div>
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<h3>
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<span class="mim-font">
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JUVENILE MYELOMONOCYTIC LEUKEMIA; JMML
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</span>
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</h3>
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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-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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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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LEUKEMIA, JUVENILE MYELOMONOCYTIC
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</span>
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</h4>
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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-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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LEUKEMIA, CHRONIC MYELOMONOCYTIC, INCLUDED; CMML, 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>SNOMEDCT:</strong> 127225006, 128831004, 128832006, 277587001, 445227008;
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<strong>ICD10CM:</strong> C93.1, C93.10, C93.3, C93.30;
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<strong>ORPHA:</strong> 86834;
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<strong>DO:</strong> 0050458;
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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>Phenotype-Gene 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>
|
|
Phenotype <br /> mapping key
|
|
</th>
|
|
<th>
|
|
Gene/Locus
|
|
</th>
|
|
<th>
|
|
Gene/Locus <br /> MIM number
|
|
</th>
|
|
</tr>
|
|
</thead>
|
|
<tbody>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
5q31.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607785
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
ARHGAP26
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
605370
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
11q23.3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
?Juvenile myelomonocytic leukemia
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607785
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
CBL
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
165360
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
12q24.13
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic, somatic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607785
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
PTPN11
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
176876
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
<tr>
|
|
<td>
|
|
<span class="mim-font">
|
|
17q11.2
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Leukemia, juvenile myelomonocytic
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
607785
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
Autosomal dominant; Somatic mutation
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
3
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
NF1
|
|
</span>
|
|
</td>
|
|
<td>
|
|
<span class="mim-font">
|
|
613113
|
|
</span>
|
|
</td>
|
|
</tr>
|
|
|
|
</tbody>
|
|
</table>
|
|
</div>
|
|
</div>
|
|
|
|
|
|
|
|
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>TEXT</strong>
|
|
</span>
|
|
</h4>
|
|
|
|
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>A number sign (#) is used with this entry because of evidence that juvenile myelomonocytic leukemia (JMML) can be caused by germline heterozygous mutation in the CBL gene (165360) on chromosome 11q23. One such family has been reported.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Description</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Juvenile myelomonocytic leukemia is an aggressive pediatric myelodysplastic syndrome (MDS)/myeloproliferative disorder (MPD) characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny (Loh et al., 2009). JMML constitutes approximately 30% of childhood cases of myelodysplastic syndrome and 2% of leukemia (Hasle et al., 1999). Although JMML is a progressive and often rapidly fatal disease without hematopoietic stem cell transplantation (HSCT), some patients have been shown to have a prolonged and stable clinical course without HSCT (Niemeyer et al., 1997). Chronic myelomonocytic leukemia (CMML) is a similar disorder with later onset. Both JMML and CMML have a high frequency of mutations affecting the RAS signaling pathway and show hypersensitivity to stimulation with GM-CSF, which causes STAT5 (601511) hyperphosphorylation (Loh et al., 2009). </p><p><strong><em>Genetic Heterogeneity of Juvenile Myelomonocytic Leukemia</em></strong></p><p>
|
|
In up to 60% of cases of JMML, the RAS/MAPK pathway is deregulated due to somatic mutations in the PTPN11 (176876), KRAS (190070), and NRAS (164790) genes. Additionally, both germline and somatic mutations in the CBL gene have been found in patients with JMML, indicating a frequency of 10 to 15% of JMML patients overall (Loh et al., 2009). Somatic disruptions of the GRAF gene (ARHGAP26; 605370) have also been found in patients with JMML. </p><p>About 10 to 15% of JMML cases arise in children with neurofibromatosis type I (NF1; 162200) due to germline mutations in the NF1 gene (613113). In addition, patients with Noonan syndrome (NS1, 163950; NS3, 609942) or Noonan syndrome-like disorder (NSLL; 613563) due to germline mutations in the PTPN11, KRAS2, and CBL genes, respectively, also have an increased risk of developing JMML.</p><p><strong><em>Genetic Heterogeneity of Chronic Myelomonocytic Leukemia</em></strong></p><p>
|
|
Somatic mutations in the CBL, ASXL1 (612990), TET2 (612839), and SF3B1 (605590) genes have been found in patients with CMML.</p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Clinical Features</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Pathak et al. (2015) reported a family in which 4 patients developed leukemia in the first few years of life. One patient died at age 16 months, whereas the other 3 patients were followed for 35 years. Retrospective diagnosis was consistent with JMML. Two of the patients had some persistent hematologic abnormalities into adulthood, and the third had continued splenomegaly. None had clinical features consistent with Noonan syndrome (see 613563), although 1 of the patients had dysmorphic facial features at age 18 months, including slanted palpebral fissures, small mouth, long grooved philtrum, short upturned nose, and facial hypotonia. Several other family members had acute myelomonocytic leukemia, splenomegaly, polyclonal gammopathy, and monocytosis. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Cytogenetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>In a patient with chronic myelomonocytic leukemia (CMML) with a t(5;7)(q33;q11.2) translocation, Ross et al. (1998) found fusion of the HIP1 gene (601767) to the platelet-derived growth factor-beta receptor gene (PDGFRB; 173410). They identified a chimeric transcript containing the HIP1 gene located at 7q11.2 fused to the PDGFRB gene on 5q33. The fusion gene encoded amino acids 1 to 950 of HIP1 joined in-frame to the transmembrane and tyrosine kinase domains of the PDGFRB gene. The reciprocal PDGFRB/HIP1 transcript was not expressed. The fusion protein product was a 180-kD protein when expressed in a murine hematopoietic cell line and was constitutively tyrosine phosphorylated. Furthermore, the fusion gene transformed the same mouse hematopoietic cell line to interleukin-3-independent growth. </p><p>In a patient with CMML and an acquired t(5;17)(q33;p13), Magnusson et al. (2001) demonstrated rabaptin-5 (RABEP1; 603616) as a novel partner fused in-frame to the 5-prime portion of the PDGFBR gene. The fusion protein included more than 85% of the native rabaptin-5 fused to the transmembrane and intracellular tyrosine kinase domains of PDGFRB. Rabaptin-5 is an essential and rate-limiting component of early endosomal fusion. The new fusion protein links 2 important pathways of growth regulation. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Molecular Genetics</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p><strong><em>Mutations Associated with Noonan Syndrome and JMML</em></strong></p><p>
|
|
Tartaglia et al. (2003) showed that germline mutations in PTPN11 lead to Noonan syndrome-1 (NS1; 163950) associated with JMML (T73I; 176876.0011), and that somatic mutations in PTPN11 are associated with isolated JMML. Jongmans et al. (2005) described a patient with Noonan syndrome and mild JMML who carried a mutation in the PTPN11 gene (176876.0011). </p><p>Schubbert et al. (2006) described a 3-month-old female with Noonan syndrome-3 (NS3; 609942) and a severe clinical phenotype who presented with a JMML-like myeloproliferative disorder. The patient was heterozygous for a mutation in the KRAS gene (T58I; 190070.0011). This mutation was also present in her buccal cells, but was absent in parental DNA. </p><p>De Filippi et al. (2009) reported a boy who presented in infancy with JMML but was later noted to have dysmorphic features suggestive of, but not diagnostic of, Noonan syndrome (NS6; 613224). Features included short stature, relative macrocephaly, high forehead, epicanthal folds, long eyebrows, low nasal bridge, low-set ears, 2 cafe-au-lait spots, and low scores on performance tasks. Cardiac studies were normal. Genetic analysis revealed a de novo germline heterozygous mutation in the NRAS gene (G13D; 164790.0003). </p><p>In 3 unrelated patients with a Noonan syndrome-like disorder (613563) who developed JMML, Perez et al. (2010) identified a heterozygous germline mutation in the CBL gene (Y371H; 165360.0005). The mutation occurred de novo in 2 patients and was inherited from an unaffected father in 1 patient. Leukemia cells of all patients showed somatic loss of heterozygosity at chromosome 11q23, including the CBL gene. The findings indicated that germline heterozygous mutations in the CBL gene are associated with predisposition for the development of JMML. </p><p>In 27 of 159 leukemia samples from patients with JMML, Loh et al. (2009) identified 25 homozygous and 2 heterozygous mutations in the CBL gene. The mutations were located throughout the linker and RING finger domains, and Y371H was the most common mutation. Leukemic cells from 3 patients examined in detail had acquired isodisomy of chromosome 11q including the CBL gene. Each of these 3 patients had a heterozygous germline CBL mutation, whereas their tumor cells had homozygous mutations. Leukemic cells exhibited CFU-GM hypersensitivity and high levels of STAT5 (601511) in response to GM-CSF. These findings indicated that reduplication of an inherited CBL mutation in a pluripotent hematopoietic stem cell confers a selective advantage for the homozygous state. Loh et al. (2009) estimated the frequency of CBL mutations to be 10 to 15% of JMML patients overall. They did not find CBL mutations in JMML patients with known PTPN11/RAS mutation, indicating that CBL and PTPN11/RAS mutations are mutually exclusive. The finding that heterozygous germline mutations may predispose to development of JMML suggested that CBL acts as a tumor suppressor gene. </p><p><strong><em>Isolated Juvenile or Chronic Myelomonocytic Leukemia</em></strong></p><p>
|
|
In 3 affected members of a family with JMML, Pathak et al. (2015) identified a germline heterozygous missense mutation in the CBL gene (Y371C; 165360.0009). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was also present in 4 family members without JMML, consistent with incomplete penetrance. Structural modeling predicted that the mutation would abrogate the ability of the mutant protein to adopt a conformation that would permit protein ubiquitination. Functional studies of the variant were not performed. </p><p>In white blood cells derived from 11 patients with juvenile myelomonocytic leukemia, Matsuda et al. (2007) identified 3 different somatic heterozygous mutations in the KRAS gene (G13D, 190070.0003; G12D, 190070.0005; and G12S, 190070.0007) and 5 different somatic mutations in the NRAS gene (see, e.g., G12D, 164790.0007 and G13D, 164790.0003). Each patient carried a single somatic mutation. The patients were ascertained from a cohort of 80 children with JMML. </p><p>Jankowska et al. (2009) identified recurrent areas of somatic copy number-neutral loss of heterozygosity (LOH) and deletions of chromosome 4q24 in patients with MDS/MPD. Subsequent analysis identified somatic mutations in the TET2 gene (612839) in 6 of 17 cases of chronic myelomonocytic leukemia. </p><p>Abdel-Wahab et al. (2009) identified somatic mutations in the TET2 gene in 29 (42%) of 69 CMML. </p><p>Gelsi-Boyer et al. (2009) presented evidence that the ASXL1 gene (612990) may act as a tumor suppressor in myeloid malignancies. They identified somatic ASXL1 mutations were also found in 19 (43%) of 44 chronic myelomonocytic leukemia samples. </p><p>Loh et al. (2009) found isolated CBL mutations in 4 of 44 samples from patients with CMML, which shares features with JMML. </p><p>Muramatsu et al. (2010) identified uniparental disomy of 11q23 in leukemic cells from 4 of 49 patients with JMML. Mutation analysis of the CBL gene identified somatic mutations in 5 (10%) of 49 patients. Mutations in the PTPN11 gene were found in 26 (53%), whereas NRAS and KRAS mutations were found in 2 (4%) and 1 (2%) patient, respectively. None of the patients had mutations in the TET2 gene (612839), which had previously been shown to be present in a significant proportion of patients with MDS/MPD, including CMML (see Jankowska et al., 2009). Eighteen (37%) of the 49 patients with JMML studied by Muramatsu et al. (2010) did not have any of the known pathogenic defects. </p><p>Klinakis et al. (2011) identified novel somatic-inactivating Notch (see 190198) pathway mutations in a fraction of patients with CMML. Inactivation of Notch signaling in mouse hematopoietic stem cells resulted in aberrant accumulation of granulocyte/monocyte progenitors, extramedullary hematopoiesis, and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1 (139605). Klinakis et al. (2011) concluded that their studies identified a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggested that the Notch pathway can play both tumor-promoting and -suppressive roles within the same tissue. </p><p>Sakaguchi et al. (2013) performed whole-exome sequencing for paired tumor-normal DNA from 13 individuals with JMML (cases), followed by deep sequencing of 8 target genes in 92 tumor samples. JMML was characterized by a paucity of gene mutations (0.85 nonsilent mutations per sample) with somatic or germline RAS pathway involvement in 82 cases (89%). The SETBP1 (611060) and JAK3 (600173) mutations were among common targets for secondary mutations. Mutations in JAK3 were often subclonal, and Sakaguchi et al. (2013) hypothesized that they may be involved in the progression rather than the initiation of leukemia; these mutations associated with poor clinical outcomes. </p><p><strong><em>Exclusion Studies</em></strong></p><p>
|
|
Yoshida et al. (2008) excluded mutation in the SIPA1 gene (602180) as a cause of JMML in 16 specimens obtained from patients with the disorder who did not have mutations in the KRAS, NRAS, or PTPN11 genes. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>Genotype/Phenotype Correlations</strong>
|
|
</span>
|
|
</h4>
|
|
</div>
|
|
|
|
|
|
|
|
<span class="mim-text-font">
|
|
<p>Matsuda et al. (2007) reported 3 patients with an NRAS or KRAS gly12-to-ser (G12S) mutation who showed spontaneous improvement of hematologic abnormalities lasting for 2 to 4 years with neither intensive therapy nor HSCT. They suggested that the mild course correlated with the G12S RAS mutation and recommended that patients found to have this mutation receive close follow-up but no chemotherapy. Flotho et al. (2008) viewed the recommendation of Matsuda et al. (2007) as premature. They reviewed 50 patients with JMML who were not given HSCT within the first 3 years after diagnosis; of these, 17 survived without treatment from 4 to 21 years. Six of 7 carried a RAS mutation different from R12S. </p>
|
|
</span>
|
|
<div>
|
|
<br />
|
|
</div>
|
|
|
|
|
|
|
|
</div>
|
|
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|
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|
|
|
|
|
|
<div>
|
|
<h4>
|
|
<span class="mim-font">
|
|
<strong>REFERENCES</strong>
|
|
</span>
|
|
</h4>
|
|
<div>
|
|
<p />
|
|
</div>
|
|
|
|
<div>
|
|
<ol>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Abdel-Wahab, O., Mullally, A., Hedvat, C., Garcia-Manero, G., Patel, J., Wadleigh, M., Malinge, S., Yao, J., Kilpivaara, O., Bhat, R., Huberman, K., Thomas, S., and 12 others.
|
|
<strong>Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies.</strong>
|
|
Blood 114: 144-147, 2009.
|
|
|
|
|
|
[PubMed: 19420352]
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|
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|
|
[Full Text: https://doi.org/10.1182/blood-2009-03-210039]
|
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
De Filippi, P., Zecca, M., Lisini, D., Rosti, V., Cagioni, C., Carlo-Stella, C., Radi, O., Veggiotti, P., Mastronuzzi, A., Acquaviva, A., D'Ambrosio, A., Locatelli, F., Danesino, C.
|
|
<strong>Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia.</strong>
|
|
Brit. J. Haemat. 147: 706-709, 2009.
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|
|
|
|
|
[PubMed: 19775298]
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|
[Full Text: https://doi.org/10.1111/j.1365-2141.2009.07894.x]
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|
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</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Flotho, C., Kratz, C. P., Bergstrasser, E., Hasle, H., Stary, J., Trebo, M., van den Heuvel-Eibrink, M. M., Wojcik, D., Zecca, M., Locatelli, F., Niemeyer, C. M.
|
|
<strong>Genotype-phenotype correlation in cases of juvenile myelomonocytic leukemia with clonal RAS mutations. (Letter)</strong>
|
|
Blood 111: 966-967, 2008.
|
|
|
|
|
|
[PubMed: 18182584]
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|
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|
|
[Full Text: https://doi.org/10.1182/blood-2007-09-111831]
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|
|
</p>
|
|
</li>
|
|
|
|
<li>
|
|
<p class="mim-text-font">
|
|
Gelsi-Boyer, V., Trouplin, V., Adelaide, J., Bonansea, J., Cervera, N., Carbuccia, N., Lagarde, A., Prebet, T., Nezri, M., Sainty, D., Olschwang, S., Xerri, L., Chaffanet, M., Mozziconacci, M.-J., Vey, N., Birnbaum, D.
|
|
<strong>Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia.</strong>
|
|
Brit. J. Haemat. 145: 788-800, 2009.
|
|
|
|
|
|
[PubMed: 19388938]
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|
[Full Text: https://doi.org/10.1111/j.1365-2141.2009.07697.x]
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|
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</p>
|
|
</li>
|
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<li>
|
|
<p class="mim-text-font">
|
|
Hasle, H., Arico, M., Basso, G., Biondi, A., Rajnoldi, A. C., Creutzig, U., Fenu, S., Fonatsch, C., Haas, O. A., Harbott, J., Kardos, G., Kerndrup, G., and 11 others.
|
|
<strong>Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7.</strong>
|
|
Leukemia 13: 376-385, 1999.
|
|
|
|
|
|
[PubMed: 10086728]
|
|
|
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|
|
[Full Text: https://doi.org/10.1038/sj.leu.2401342]
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</p>
|
|
</li>
|
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|
<li>
|
|
<p class="mim-text-font">
|
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