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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>CEBPA-Associated Familial Acute Myeloid Leukemia (AML) - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="CEBPA-Associated Familial Acute Myeloid Leukemia (AML)">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2021/02/18">
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<meta name="citation_author" content="Kiran Tawana">
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<meta name="citation_author" content="Jude Fitzgibbon">
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<meta name="citation_pmid" content="20963938">
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<meta name="citation_keywords" content="CEBPA-Dependent Familial Acute Myeloid Leukemia">
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<meta name="citation_keywords" content="CEBPA-Dependent Familial Acute Myeloid Leukemia">
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<meta name="citation_keywords" content="CCAAT/enhancer-binding protein alpha">
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<meta name="citation_keywords" content="CEBPA">
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<meta name="citation_keywords" content="CEBPA-Associated Familial Acute Myeloid Leukemia (AML)">
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<meta name="DC.Title" content="CEBPA-Associated Familial Acute Myeloid Leukemia (AML)">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Kiran Tawana">
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<meta name="DC.Contributor" content="Jude Fitzgibbon">
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<meta name="DC.Date" content="2021/02/18">
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<meta name="description" content="CEBPA-associated familial acute myeloid leukemia (AML) is defined as the presence of a heterozygous germline CEBPA pathogenic variant in an individual with AML and/or family in which more than one individual has AML. In contrast, sporadic CEBPA-associated AML is defined as AML in which a CEBPA pathogenic variant(s) is identified in leukemic cells but not in the non-leukemic cells. In the majority of individuals, the age of onset of familial AML appears to be earlier than sporadic AML; disease onset has been reported in persons as young as age 1.8 years and up to age 50 years. The prognosis of CEBPA-associated familial AML appears to be favorable compared with sporadic CEBPA-associated AML. Individuals with CEBPA-associated familial AML who have been cured of their initial disease may be at greater risk of developing additional independent leukemic episodes, in addition to the risk of relapse from preexisting clones.">
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<meta name="og:description" content="CEBPA-associated familial acute myeloid leukemia (AML) is defined as the presence of a heterozygous germline CEBPA pathogenic variant in an individual with AML and/or family in which more than one individual has AML. In contrast, sporadic CEBPA-associated AML is defined as AML in which a CEBPA pathogenic variant(s) is identified in leukemic cells but not in the non-leukemic cells. In the majority of individuals, the age of onset of familial AML appears to be earlier than sporadic AML; disease onset has been reported in persons as young as age 1.8 years and up to age 50 years. The prognosis of CEBPA-associated familial AML appears to be favorable compared with sporadic CEBPA-associated AML. Individuals with CEBPA-associated familial AML who have been cured of their initial disease may be at greater risk of developing additional independent leukemic episodes, in addition to the risk of relapse from preexisting clones.">
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yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK47457_"><span class="title" itemprop="name"><i>CEBPA-</i>Associated Familial Acute Myeloid Leukemia (AML)</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: <i>CEBPA</i>-Dependent Familial Acute Myeloid Leukemia</div><p class="contribs">Tawana K, Fitzgibbon J.</p><p class="fm-aai"><a href="#_NBK47457_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 22 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="cebpa-aml.Summary" itemprop="description"><h2 id="_cebpa-aml_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p><i>CEBPA-</i>associated familial acute myeloid leukemia (AML) is defined as the presence of a heterozygous germline <i>CEBPA</i> pathogenic variant in an individual with AML and/or family in which more than one individual has AML. In contrast, sporadic <i>CEBPA</i>-associated AML is defined as AML in which a <i>CEBPA</i> pathogenic variant(s) is identified in leukemic cells but not in the non-leukemic cells. In the majority of individuals, the age of onset of familial AML appears to be earlier than sporadic AML; disease onset has been reported in persons as young as age 1.8 years and up to age 50 years. The prognosis of <i>CEBPA-</i>associated familial AML appears to be favorable compared with sporadic <i>CEBPA</i>-associated AML. Individuals with <i>CEBPA</i>-associated familial AML who have been cured of their initial disease may be at greater risk of developing additional independent leukemic episodes, in addition to the risk of relapse from preexisting clones.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of <i>CEBPA</i>-associated familial AML is established by identification of a heterozygous germline <i>CEBPA</i> pathogenic variant in a specimen that contains only non-leukemic cells from an individual and/or family with AML.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations</i>: Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy. Hematopoietic stem cell transplantation (HSCT) from a volunteer unrelated donor or appropriately screened family member should be reserved for individuals failing to achieve remission following standard induction therapy or for disease recurrence. Whenever possible, persons with AML should be treated as part of a clinical trial protocol.</p><p><i>Surveillance</i>: Similar to that for other forms of AML; because of the increased risk of late leukemia recurrence in persons with familial AML, lifelong surveillance is recommended. Asymptomatic individuals should have a CBC every six to 12 months and bone marrow examination for CBC abnormalities.</p><p><i>Agents/circumstances to avoid</i>: Use of sib or related donors for HSCT without prior assessment of the germline <i>CEBPA</i> pathogenic variant in the donor.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Predisposition to <i>CEBPA-</i>associated familial AML is inherited in an autosomal dominant manner. Most individuals diagnosed with <i>CEBPA</i>-associated familial AML have had an affected parent who shares the germline pathogenic variant. Germline <i>CEBPA</i> pathogenic variants exhibit complete or near-complete penetrance for the development of AML in families reported to date. Each child of an affected individual has a 50% chance of inheriting the germline pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the germline <i>CEBPA</i> pathogenic variant in the family is known.</p></div></div><div id="cebpa-aml.Diagnosis"><h2 id="_cebpa-aml_Diagnosis_">Diagnosis</h2><div id="cebpa-aml.Suggestive_Findings"><h3>Suggestive Findings</h3><p><i>CEBPA-</i>associated familial acute myeloid leukemia (AML) <b>should be suspected</b> in individuals with the following clinical and supportive laboratory findings.</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div>Individuals with AML who also have a family history of AML</div></li><li class="half_rhythm"><div>Individuals who have developed AML at an early age (<50 years)</div></li></ul><p>
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<b>Supportive laboratory findings</b>
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</p><ul><li class="half_rhythm"><div>Typically, individuals with AML presenting before age 50 years with pathogenic variants in both copies of <i>CEBPA</i> (<i>CEBPA</i> double mutation [<i>CEBPA</i>dm]) in tumor DNA</div></li><li class="half_rhythm"><div>In the majority of individuals, a normal karyotype detected in leukemic cells</div></li><li class="half_rhythm"><div>A preponderance of French-American-British Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts</div></li><li class="half_rhythm"><div>Auer rods seen in blasts (i.e., abnormal, needle-shaped, or round, light blue- or pink-staining inclusions found in the cytoplasm of leukemic cells)</div></li><li class="half_rhythm"><div>Aberrant CD7 expression on blasts as demonstrated by flow cytometry</div></li></ul><p>For this <i>GeneReview</i>, the following definitions apply:</p><ul><li class="half_rhythm"><div><b><i>CEBPA</i>-associated familial AML</b> is defined by the presence of a heterozygous germline <i>CEBPA</i> pathogenic variant. A germline pathogenic variant may be inherited or <i>de novo</i>.</div></li><li class="half_rhythm"><div><b>Sporadic <i>CEBPA-</i>associated</b>
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<b>AML</b> is defined as AML in which a somatic <i>CEBPA</i> pathogenic variant(s) is acquired in leukemic cells alone; these variants are absent in all of the individual's non-leukemic cells (see <a href="#cebpa-aml.Molecular_Genetics">Molecular Genetics</a>).</div></li></ul></div><div id="cebpa-aml.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of <i>CEBPA</i>-associated familial AML <b>is established</b> in a proband with a heterozygous germline <i>CEBPA</i> pathogenic variant (see <a href="/books/NBK47457/table/cebpa-aml.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobcebpaamlTmoleculargenetictestingus">Table 1</a>). Because <i>CEBPA</i>-associated familial AML develops from cells that have a pathogenic (cancer-predisposing) variant in both copies of <i>CEBPA,</i> leukemic cells frequently demonstrate both a germline and a somatic <i>CEBPA</i> variant. The germline pathogenic variant is typically a frameshift variant located in the <i>CEBPA</i> region encoding the N-terminal C/EBPα protein, while the somatic pathogenic variant acquired in leukemic cells is typically in the region encoding the C terminal (see <a href="#cebpa-aml.Molecular_Genetics">Molecular Genetics</a>).</p><p>Note: In the literature, the terms <i>CEBPA</i>dm and <i>CEBPA</i>sm may be used. These terms refer to leukemic cells with biallelic <i>CEBPA</i> pathogenic variants ("<i>d</i>ouble <i>m</i>utation") or a heterozygous <i>CEBPA</i> pathogenic variant ("<i>s</i>ingle <i>m</i>utation"). These terms do not specify if the pathogenic variant is germline or somatic (see <a href="#cebpa-aml.Molecular_Pathogenesis">Molecular Pathogenesis</a>).</p><p>Molecular testing approaches include <b>single-gene testing</b> and use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>CEBPA</i> is performed in a non-leukemic specimen.</div><div class="half_rhythm">Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing an uninvolved specimen, such as cells obtained by buccal swab/saliva, skin biopsy, or cultured dendritic cells, is imperative. (2) It should be noted that <i>CEBPA</i> pathogenic variants are found in the leukemic cells of approximately 9% of persons with AML (with heterozygous and biallelic pathogenic variants in similar proportions) [<a class="bibr" href="#cebpa-aml.REF.green.2010.2739" rid="cebpa-aml.REF.green.2010.2739">Green et al 2010</a>, <a class="bibr" href="#cebpa-aml.REF.dufour.2010.570" rid="cebpa-aml.REF.dufour.2010.570">Dufour et al 2010</a>, <a class="bibr" href="#cebpa-aml.REF.fasan.2014.794" rid="cebpa-aml.REF.fasan.2014.794">Fasan et al 2014</a>]. However, few of these individuals have a germline <i>CEBPA</i> pathogenic variant. (3) Testing of blood or bone marrow during complete remission from AML may also be performed to detect a germline variant. The percentage of residual leukemic cells in remission samples is negligible, ensuring that somatic variants are not falsely classified as germline variants.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A multigene panel</b> that includes <i>CEBPA</i> and other genes of interest (see <a href="#cebpa-aml.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered, although care should be taken to ensure that coverage is adequate (due to the high GC content of the coding region: 75%) and that large insertions, such as those targeting the C terminal, are accurately detected with high-throughput methods. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcebpaamlTmoleculargenetictestingus"><a href="/books/NBK47457/table/cebpa-aml.T.molecular_genetic_testing_us/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobcebpaamlTmoleculargenetictestingus"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cebpa-aml.T.molecular_genetic_testing_us"><a href="/books/NBK47457/table/cebpa-aml.T.molecular_genetic_testing_us/?report=objectonly" target="object" rid-ob="figobcebpaamlTmoleculargenetictestingus">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in <i>CEBPA</i>-Associated Familial Acute Myeloid Leukemia </p></div></div></div></div><div id="cebpa-aml.Clinical_Characteristics"><h2 id="_cebpa-aml_Clinical_Characteristics_">Clinical Characteristics</h2><div id="cebpa-aml.Clinical_Description"><h3>Clinical Description</h3><p>To date, fourteen families with <i>CEBPA</i>-associated familial acute myeloid leukemia (AML) have been reported [<a class="bibr" href="#cebpa-aml.REF.smith.2004.2403" rid="cebpa-aml.REF.smith.2004.2403">Smith et al 2004</a>, <a class="bibr" href="#cebpa-aml.REF.sellick.2005.1276" rid="cebpa-aml.REF.sellick.2005.1276">Sellick et al 2005</a>, <a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al 2008</a>, <a class="bibr" href="#cebpa-aml.REF.renneville.2009.804" rid="cebpa-aml.REF.renneville.2009.804">Renneville et al 2009</a>, <a class="bibr" href="#cebpa-aml.REF.nanri.2010.237" rid="cebpa-aml.REF.nanri.2010.237">Nanri et al 2010</a>, <a class="bibr" href="#cebpa-aml.REF.stelljes.2011.1209" rid="cebpa-aml.REF.stelljes.2011.1209">Stelljes et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.taskesen.2011.2469" rid="cebpa-aml.REF.taskesen.2011.2469">Taskesen et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.xiao.2011.5257" rid="cebpa-aml.REF.xiao.2011.5257">Xiao et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.debeljak.2013.e73" rid="cebpa-aml.REF.debeljak.2013.e73">Debeljak et al 2013</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>, <a class="bibr" href="#cebpa-aml.REF.pathak.2016.846" rid="cebpa-aml.REF.pathak.2016.846">Pathak et al 2016</a>, <a class="bibr" href="#cebpa-aml.REF.yan.2016.652" rid="cebpa-aml.REF.yan.2016.652">Yan et al 2016</a>, <a class="bibr" href="#cebpa-aml.REF.mendoza.2021.1251" rid="cebpa-aml.REF.mendoza.2021.1251">Mendoza et al 2021</a>], the majority of which manifest a highly penetrant (>80%) AML phenotype. More recently, germline <i>CEBPA</i> pathogenic variants located outside of the N terminal appear less penetrant, with approximately 50% of individuals with a heterozygous germline pathogenic variant developing AML. Given the limited number of family members tested in historical studies, it is possible that the true penetrance of AML may vary [<a class="bibr" href="#cebpa-aml.REF.pabst.2009.5303" rid="cebpa-aml.REF.pabst.2009.5303">Pabst & Mueller 2009</a>].</p><p>The age of onset of <i>CEBPA</i>-associated familial AML is variable, but appears to be earlier than in sporadic AML. Disease onset has been reported in persons as young as 1.8 years [<a class="bibr" href="#cebpa-aml.REF.debeljak.2013.e73" rid="cebpa-aml.REF.debeljak.2013.e73">Debeljak et al 2013</a>] and older than 45 years [<a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al 2008</a>]. By contrast, the median age at diagnosis of persons with sporadic AML is 65 years.</p><p>Individuals commonly present with AML (of French-American-British subtypes M1, M2 or M4) following the acquisition of a somatic <i>CEBPA</i> pathogenic variant and additional somatic pathogenic variants, frequently involving <i>GATA2</i> (zinc finger 1), <i>WT1</i>, <i>TET2</i>, <i>EZH2</i>, and <i>NRAS</i> [<a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>].</p><p>From an analysis of ten pedigrees with <i>CEBPA</i>-associated familial AML, the disease follows a course similar to sporadic AML with biallelic <i>CEBPA</i> pathogenic variants (<i>CEBPA</i>dm)<i>.</i> The prognosis of individuals with familial AML appears to be favorable, with ten-year overall survival (OS) reaching 67%, compared to 54% OS in younger adults with sporadic AML associated with two <i>CEBPA</i> pathogenic variants and 29% OS with sporadic AML associated with a single <i>CEBPA</i> pathogenic variant [<a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>].</p><p>Individuals with <i>CEBPA</i>-associated familial AML who have been cured of their initial disease may be at greater risk of developing recurrent, independent leukemic episodes that are characterized by a different somatic <i>CEBPA</i> pathogenic variant from that observed in the original tumor clone. This phenomenon contrasts with relapse in individuals with sporadic AML, where <i>CEBPA</i> pathogenic variants are stable throughout the disease course [<a class="bibr" href="#cebpa-aml.REF.tiesmeier.2003.413" rid="cebpa-aml.REF.tiesmeier.2003.413">Tiesmeier et al 2003</a>, <a class="bibr" href="#cebpa-aml.REF.shih.2006.604" rid="cebpa-aml.REF.shih.2006.604">Shih et al 2006</a>, <a class="bibr" href="#cebpa-aml.REF.hollink.2011.384" rid="cebpa-aml.REF.hollink.2011.384">Hollink et al 2011</a>].</p></div><div id="cebpa-aml.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>To date, the majority of germline <i>CEBPA</i> pathogenic variants are frameshift variants located in the N terminal of the gene (preceding the internal start codon, located at codon 120).</p></div><div id="cebpa-aml.Penetrance"><h3>Penetrance</h3><p>Analysis of pedigrees reported to date suggests that germline <i>CEBPA</i> pathogenic variants exhibit high penetrance for the development of AML [<a class="bibr" href="#cebpa-aml.REF.nickels.2013.254" rid="cebpa-aml.REF.nickels.2013.254">Nickels et al 2013</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>]. The penetrance of pathogenic variants may vary within and between families; data from ten families with germline <i>CEBPA</i> pathogenic variants affecting the N terminal (preceding the internal start codon, located at codon 120) revealed that more than 80% of confirmed or presumed obligate adult heterozygotes have developed disease to date [<a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>]. Germline <i>CEBPA</i> pathogenic variants located outside of the N terminal (e.g., within the transactivation or leucine zipper domains) appear less penetrant, with approximately 50% of individuals with a heterozygous germline pathogenic variant developing AML [<a class="bibr" href="#cebpa-aml.REF.pathak.2016.846" rid="cebpa-aml.REF.pathak.2016.846">Pathak et al 2016</a>, <a class="bibr" href="#cebpa-aml.REF.mendoza.2021.1251" rid="cebpa-aml.REF.mendoza.2021.1251">Mendoza et al 2021</a>].</p></div><div id="cebpa-aml.Nomenclature"><h3>Nomenclature</h3><p>International recognition of inherited hematologic malignancies has grown significantly following the WHO classification in 2016, which incorporated myeloid neoplasms associated with germline <i>ANKRD26</i>, <i>CEBPA</i>, <a href="/books/n/gene/ddx41-mds/?report=reader"><i>DDX41</i></a>, <i>GATA2</i>, and <a href="/books/n/gene/runx1/?report=reader"><i>RUNX1</i></a> pathogenic variants [<a class="bibr" href="#cebpa-aml.REF.arber.2016.2391" rid="cebpa-aml.REF.arber.2016.2391">Arber et al 2016</a>]. The WHO classification also defined AML with biallelic <i>CEBPA</i> pathogenic variants (<i>CEBPA</i>dm [<i>CEBPA</i> double-mutated]) as a distinct prognostic entity. Of note, there was no distinction between sporadic and familial AML within this category.</p></div><div id="cebpa-aml.Prevalence"><h3>Prevalence</h3><p><i>CEBPA-</i>associated familial AML is very rare, with only fourteen pedigrees reported [<a class="bibr" href="#cebpa-aml.REF.smith.2004.2403" rid="cebpa-aml.REF.smith.2004.2403">Smith et al 2004</a>, <a class="bibr" href="#cebpa-aml.REF.sellick.2005.1276" rid="cebpa-aml.REF.sellick.2005.1276">Sellick et al 2005</a>, <a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al 2008</a>, <a class="bibr" href="#cebpa-aml.REF.renneville.2009.804" rid="cebpa-aml.REF.renneville.2009.804">Renneville et al 2009</a>, <a class="bibr" href="#cebpa-aml.REF.nanri.2010.237" rid="cebpa-aml.REF.nanri.2010.237">Nanri et al 2010</a>, <a class="bibr" href="#cebpa-aml.REF.stelljes.2011.1209" rid="cebpa-aml.REF.stelljes.2011.1209">Stelljes et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.taskesen.2011.2469" rid="cebpa-aml.REF.taskesen.2011.2469">Taskesen et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.xiao.2011.5257" rid="cebpa-aml.REF.xiao.2011.5257">Xiao et al 2011</a>, <a class="bibr" href="#cebpa-aml.REF.debeljak.2013.e73" rid="cebpa-aml.REF.debeljak.2013.e73">Debeljak et al 2013</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>, <a class="bibr" href="#cebpa-aml.REF.pathak.2016.846" rid="cebpa-aml.REF.pathak.2016.846">Pathak et al 2016</a>, <a class="bibr" href="#cebpa-aml.REF.mendoza.2021.1251" rid="cebpa-aml.REF.mendoza.2021.1251">Mendoza et al 2021</a>].</p><p><a class="bibr" href="#cebpa-aml.REF.taskesen.2011.2469" rid="cebpa-aml.REF.taskesen.2011.2469">Taskesen et al [2011]</a> identified a germline <i>CEBPA</i> pathogenic variant in five of 71 individuals (7%); two of the five had a family history of AML.</p></div></div><div id="cebpa-aml.Genetically_Related_Allelic_Di"><h2 id="_cebpa-aml_Genetically_Related_Allelic_Di_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>CEBPA</i>.</p><p>Note: Sporadic <i>CEBPA-</i>associated acute myeloid leukemia (AML) is defined as AML in which a somatic <i>CEBPA</i> pathogenic variant(s) is acquired in leukemic cells alone and not in the germline (see <a href="#cebpa-aml.Molecular_Genetics">Molecular Genetics</a>).</p></div><div id="cebpa-aml.Differential_Diagnosis"><h2 id="_cebpa-aml_Differential_Diagnosis_">Differential Diagnosis</h2><p>The differential diagnosis for <i>CEBPA-</i>associated familial acute myeloid leukemia (AML) includes the following:</p><ul><li class="half_rhythm"><div>Hereditary disorders associated with an increased risk of myeloid malignancy (e.g., <a href="/books/n/gene/runx1/?report=reader"><i>RUNX1</i> familial platelet disorder with associated myeloid malignancy</a>, <a href="/books/n/gene/ddx41-mds/?report=reader"><i>DDX41</i>-associated familial myelodysplastic syndrome and acute myeloid leukemia</a>)</div></li><li class="half_rhythm"><div>Sporadic AML with somatic <i>CEBPA</i> pathogenic variant(s)</div></li><li class="half_rhythm"><div>AML secondary to environmental exposures (e.g., benzene, radiation, chemotherapy)</div></li></ul><p>Note: AML is a relatively rare disorder (~13,300 cases/year in the US); therefore, the more affected individuals in a family (and the closer the relationships), the greater the likelihood of a common cause (i.e., a heritable predisposition or a common exposure) [<a class="bibr" href="#cebpa-aml.REF.owen.2008.123" rid="cebpa-aml.REF.owen.2008.123">Owen et al 2008</a>].</p></div><div id="cebpa-aml.Management"><h2 id="_cebpa-aml_Management_">Management</h2><div id="cebpa-aml.Evaluations_Following_Initial"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs of an individual newly diagnosed with <i>CEBPA</i>-associated familial acute myeloid leukemia (AML), the evaluations summarized in <a href="/books/NBK47457/table/cebpa-aml.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobcebpaamlTrecommendedevaluationsfoll">Table 2</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcebpaamlTrecommendedevaluationsfoll"><a href="/books/NBK47457/table/cebpa-aml.T.recommended_evaluations_foll/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobcebpaamlTrecommendedevaluationsfoll"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cebpa-aml.T.recommended_evaluations_foll"><a href="/books/NBK47457/table/cebpa-aml.T.recommended_evaluations_foll/?report=objectonly" target="object" rid-ob="figobcebpaamlTrecommendedevaluationsfoll">Table 2. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with <i>CEBPA</i>-Associated Familial Acute Myeloid Leukemia </p></div></div></div><div id="cebpa-aml.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><p>Management of <i>CEBPA-</i>associated familial AML does not differ from that of sporadic <i>CEBPA-</i>associated AML [<a class="bibr" href="#cebpa-aml.REF.d_hner.2017.424" rid="cebpa-aml.REF.d_hner.2017.424">Döhner et al 2017</a>] (see also <a href="https://www.nccn.org/professionals/physician_gls/default.aspx#site" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCCN Clinical Practice Guidelines in Oncology</a>; no-fee registration and login required).</p><p>Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without hematopoietic stem cell transplantation (HSCT) according to clinical, cytogenetic, and molecular risk. Specific treatment strategies are based on characteristics of the individual, response to chemotherapy, treatment setting, and protocol (if the individual is enrolled in a clinical trial). Note: Whenever possible, persons with AML should be treated as part of a clinical trial protocol.</p><p>Germline variants should be investigated and excluded in donors prior to consideration of HSCT using sib/related donors.</p><p>Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics.</p><p>Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods (<a href="https://www.nccn.org/professionals/physician_gls/default.aspx#site" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCCN Clinical Practice Guidelines in Oncology</a>; no-fee registration and login required).</p><p>Relapses are treated with cytarabine-based salvage chemotherapy followed by allogeneic HSCT (if a suitable donor is available and if cure is the intent of treatment).</p></div><div id="cebpa-aml.Surveillance"><h3>Surveillance</h3><p><b>Affected individuals.</b> Surveillance for <i>CEBPA</i>-associated familial AML is similar to that for other forms of AML. There are no generally accepted minimal residual disease (MRD) markers in <i>CEBPA-</i>associated AML.</p><p>Individuals are monitored and evaluated in accordance with administered treatment, clinical course, symptoms, and protocol, if enrolled in clinical trials. When complete remission is achieved and intensification therapy is complete, individuals are monitored with:</p><ul><li class="half_rhythm"><div>CBC and platelet counts every one to three months for two years with the frequency decreasing to every three to six months for up to five years;</div></li><li class="half_rhythm"><div>Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.</div></li></ul><p>Note: The use of flow cytometry for MRD monitoring is controversial.</p><p>Individuals with a germline <i>CEBPA</i> pathogenic variant who are cured of their initial disease episode may be at risk for new leukemic episodes, often occurring after a prolonged period of remission (>3 years post presentation) [<a class="bibr" href="#cebpa-aml.REF.pabst.2009.1343" rid="cebpa-aml.REF.pabst.2009.1343">Pabst et al 2009</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al 2015</a>]. In light of these data, lifelong clinical surveillance is warranted to ensure prompt recognition and appropriate management of disease recurrence. Repeat testing of <i>CEBPA</i> in tumor DNA at AML recurrence is important to help distinguish conventional relapse from new, independent leukemic episodes.</p><p><b>Asymptomatic individuals</b> with a germline <i>CEBPA</i> pathogenic variant:</p><ul><li class="half_rhythm"><div>CBC every six to 12 months</div></li><li class="half_rhythm"><div>Bone marrow examination for those with CBC abnormalities</div></li></ul></div><div id="cebpa-aml.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Use of sib or related donors for HSCT without prior assessment of the germline <i>CEBPA</i> pathogenic variant in the donor should be avoided.</p></div><div id="cebpa-aml.Evaluation_of_Relatives_at_Ris"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from clinical monitoring. Clinical monitoring may enable earlier diagnosis (and treatment) of AML, hence minimizing the risks associated with delayed presentation (e.g., severe anemia, neutropenic sepsis, and severe hemorrhage).</p><p>Note:</p><ul><li class="half_rhythm"><div>There are currently no preemptive treatments available for asymptomatic individuals who have a germline <i>CEBPA</i> pathogenic variant.</div></li><li class="half_rhythm"><div>To date, all individuals with germline <i>CEBPA</i> pathogenic variants have presented with overt AML without any preceding blood count abnormalities or myelodysplasia; this is in contrast with other familial leukemia syndromes such as those associated with germline <i>RUNX1</i> or <i>GATA2</i> pathogenic variants [<a class="bibr" href="#cebpa-aml.REF.tawana.2017.87" rid="cebpa-aml.REF.tawana.2017.87">Tawana et al 2017</a>].</div></li></ul><p>See <a href="#cebpa-aml.Related_Genetic_Counseling_Iss">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="cebpa-aml.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="cebpa-aml.Genetic_Counseling"><h2 id="_cebpa-aml_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="cebpa-aml.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Predisposition to <i>CEBPA-</i>associated familial acute myeloid leukemia (AML) is inherited in an autosomal dominant manner.</p></div><div id="cebpa-aml.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Most individuals diagnosed with <i>CEBPA</i>-associated familial AML inherited a <i>CEBPA</i> pathogenic variant from an affected parent.</div></li><li class="half_rhythm"><div>In rare cases, a proband may have a <i>de novo</i> germline <i>CEBPA</i> pathogenic variant.</div></li><li class="half_rhythm"><div>If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant. Note: A pathogenic variant is reported as "<i>de novo</i>" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed <i>de novo</i>" [<a class="bibr" href="#cebpa-aml.REF.richards.2015.405" rid="cebpa-aml.REF.richards.2015.405">Richards et al 2015</a>].</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism.</div></li></ul></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with <i>CEBPA-</i>associated familial AML may appear to be negative because of early death of a parent before the onset of AML or late onset of AML in a parent. Therefore, an apparently negative family history cannot be verified unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.</div></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the genetic status of the proband’s parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband has the <i>CEBPA</i> pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.</div></li><li class="half_rhythm"><div>The likelihood that a sib who inherits a familial <i>CEBPA</i> pathogenic variant will develop AML varies within and between families (ranging from ~50% to >80%) and appears to be significantly influenced by the site of the pathogenic variant (see <a href="#cebpa-aml.Penetrance">Penetrance</a>).</div></li><li class="half_rhythm"><div>If the germline <i>CEBPA</i> pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [<a class="bibr" href="#cebpa-aml.REF.rahbari.2016.126" rid="cebpa-aml.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>CEBPA</i> pathogenic variant but are clinically unaffected, sibs are still at increased risk for <i>CEBPA-</i>associated familial AML because (1) the germline pathogenic variant may demonstrate differences in disease manifestation and latency in a heterozygous parent, and (2) because of the theoretic possibility of parental somatic/germline mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with <i>CEBPA</i>-associated familial AML has a 50% chance of inheriting the germline <i>CEBPA</i> pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members of inheriting the germline <i>CEBPA</i> pathogenic variant depends on the genetic status of the proband's parents: if a parent has the <i>CEBPA</i> pathogenic variant, his or her family members may be at risk.</p></div><div id="cebpa-aml.Related_Genetic_Counseling_Iss"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#cebpa-aml.Evaluation_of_Relatives_at_Ris">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Testing of at-risk asymptomatic family members.</b> If a germline <i>CEBPA</i> pathogenic variant has been identified in a family member with AML, molecular genetic testing may be offered to at-risk family members in order to determine the need for clinical surveillance (see <a href="#cebpa-aml.Evaluation_of_Relatives_at_Ris">Evaluation of Relatives at Risk</a>).</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk in offspring of persons with known <i>CEBPA</i>-associated familial AML is before pregnancy. (Note: Molecular genetic <i>CEBPA</i> testing for the purpose of family planning is not recommended for individuals who develop AML in the absence of a molecular diagnosis of <i>CEBPA</i>-associated familial AML.)</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of <i>CEBPA</i>-associated familial AML or who are at risk of having inherited a familial <i>CEBPA</i> pathogenic variant.</div></li></ul></div><div id="cebpa-aml.Prenatal_Testing_and_Preimplan"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once a germline <i>CEBPA</i> pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for <i>CEBPA</i>-associated familial AML are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While use of prenatal testing is a personal decision, discussion of these issues may be helpful.</p></div></div><div id="cebpa-aml.Resources"><h2 id="_cebpa-aml_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/familial-acute-myeloid-leukemia-with-mutated-cebpa/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Familial acute myeloid leukemia with mutated CEBPA</a>
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</div></li></ul>
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</div><div id="cebpa-aml.Molecular_Genetics"><h2 id="_cebpa-aml_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcebpaamlmolgenTA"><a href="/books/NBK47457/table/cebpa-aml.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobcebpaamlmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cebpa-aml.molgen.TA"><a href="/books/NBK47457/table/cebpa-aml.molgen.TA/?report=objectonly" target="object" rid-ob="figobcebpaamlmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">CEBPA-Associated Familial Acute Myeloid Leukemia (AML): Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcebpaamlmolgenTB"><a href="/books/NBK47457/table/cebpa-aml.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobcebpaamlmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cebpa-aml.molgen.TB"><a href="/books/NBK47457/table/cebpa-aml.molgen.TB/?report=objectonly" target="object" rid-ob="figobcebpaamlmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for CEBPA-Associated Familial Acute Myeloid Leukemia (AML) (View All in OMIM) </p></div></div><div id="cebpa-aml.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>CEBPA</i> encodes the CCAAT/enhancer-binding protein alpha (C/EBPα), a transcription factor that plays a key role in granulocyte development. A detailed review of the role of C/EBPα in human cancer has been published [<a class="bibr" href="#cebpa-aml.REF.koschmieder.2009.619" rid="cebpa-aml.REF.koschmieder.2009.619">Koschmieder et al 2009</a>]. The role of mutation of <i>CEBPA</i> in the formation of acute myeloid leukemia (AML) is not well understood and is subject to ongoing research with several established mouse models simulating homozygous N-terminal frameshift pathogenic variants [<a class="bibr" href="#cebpa-aml.REF.kirstetter.2008.299" rid="cebpa-aml.REF.kirstetter.2008.299">Kirstetter et al 2008</a>], combined N- and C-terminal pathogenic variants [<a class="bibr" href="#cebpa-aml.REF.bereshchenko.2009.390" rid="cebpa-aml.REF.bereshchenko.2009.390">Bereshchenko et al 2009</a>], or conditional loss of C/EBPα [<a class="bibr" href="#cebpa-aml.REF.ye.2013.385" rid="cebpa-aml.REF.ye.2013.385">Ye et al 2013</a>].</p><p>Initiation of translation at two in-frame AUG start codons (nucleotides 151-153 and 508-510) results in two C/EBPα protein isoforms with different lengths (see <a href="/books/NBK47457/?report=reader#cebpa-aml.molgen.TA">Table A</a>, <b>Gene</b>). When translation initiates from the AUG at nucleotides 151-153, a 42-kd (also known as C/EBP-42) isoform a transcription factor is produced (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_004355.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_004355.2</a>). The full-length 42-kd protein contains two distinct transactivation domains (that mediate contact with transcriptional apparatus), a C-terminal basic region (DNA-binding), and a leucine zipper for dimerization. Alternatively, when translation initiates from the alternative start site at AUG at nucleotides 508-510, a 30-kd (also known as C/EBP-30) isoform b is produced that lacks the first transactivation domain and impairs interaction with the transcriptional apparatus mediating cell-cycle progression (<a href="https://www.ncbi.nlm.nih.gov/protein/NP_001272758.1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_001272758.1</a>). While both isoforms are normally translated, the 42-kd isoform is more abundant.</p><p>All reported germline pathogenic variants are small deletions, duplications, or insertions before codon 120. These result in a frameshift causing premature truncation at the N-terminal region of the full-length C/EBPα protein, with preservation of the 30-kd isoform. The 30-kd isoform is believed to inhibit the action of the 42-kd isoform in a dominant-negative manner.</p><p><b>Mechanism of disease causation.</b> Germline <i>CEBPA</i> pathogenic variants cause premature termination of the full-length C/EBPα protein, with preservation of the 30-kd isoform. The 30-kd isoform may inhibit the action of the normal 42-kd isoform (encoded by the remaining normal allele) in a dominant-negative manner. The acquisition of somatic in-frame insertions and deletions within the highly conserved C-terminal domains interferes with dimerization and DNA binding. The combination of N- and C-terminal pathogenic variants are thought to disrupt homo- and heterodimerization, cell cycle arrest, and differentiation [<a class="bibr" href="#cebpa-aml.REF.pabst.2009.5303" rid="cebpa-aml.REF.pabst.2009.5303">Pabst & Mueller 2009</a>].</p><p><b><i>CEBPA</i>-specific laboratory technical considerations.</b>
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<i>CEBPA</i> is a single-exon gene; the GC-rich coding region can interfere with PCR amplification and care should be taken to optimize diagnostic tests fully for sensitive and accurate detection of all variants.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figcebpaamlTnotablefamilialacutemyelo"><a href="/books/NBK47457/table/cebpa-aml.T.notable_familial_acute_myelo/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobcebpaamlTnotablefamilialacutemyelo"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="cebpa-aml.T.notable_familial_acute_myelo"><a href="/books/NBK47457/table/cebpa-aml.T.notable_familial_acute_myelo/?report=objectonly" target="object" rid-ob="figobcebpaamlTnotablefamilialacutemyelo">Table 3. </a></h4><p class="float-caption no_bottom_margin">Notable Familial Acute Myeloid Leukemia-Associated <i>CEBPA</i> Germline Pathogenic Variants </p></div></div></div><div id="cebpa-aml.Cancer_and_Benign_Tumors"><h3>Cancer and Benign Tumors</h3><p>
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<b>Somatic <i>CEBPA</i> pathogenic variants</b>
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</p><ul><li class="half_rhythm"><div><b><i>CEBPA-</i>associated familial AML.</b> The leukemic cells of most individuals with <i>CEBPA-</i>associated familial AML are compound heterozygous. In addition to the germline pathogenic variant in the N-terminal region, the leukemic cells commonly acquire somatic C-terminal in-frame pathogenic variant(s). Such variants disrupt the basic region and leucine zipper, impairing DNA binding as well as homo- and heterodimerization with other CEBP proteins and/or DNA binding [<a class="bibr" href="#cebpa-aml.REF.pabst.2007.6829" rid="cebpa-aml.REF.pabst.2007.6829">Pabst & Mueller 2007</a>, <a class="bibr" href="#cebpa-aml.REF.pabst.2009.5303" rid="cebpa-aml.REF.pabst.2009.5303">Pabst & Mueller 2009</a>].</div></li><li class="half_rhythm"><div><b>Sporadic <i>CEBPA-</i>associated AML.</b> This is defined as AML in which a somatic <i>CEBPA</i> pathogenic variant(s) is acquired in leukemic cells alone and not in the germline. In 45%-55% of all persons with sporadic <i>CEBPA</i>-associated AML<i>,</i> two pathogenic <i>CEBPA</i> variants are detected (<i>CEBPA</i>dm); most frequently, a frameshift N-terminal variant is combined with a C-terminal in-frame insertion or deletion [<a class="bibr" href="#cebpa-aml.REF.green.2010.2739" rid="cebpa-aml.REF.green.2010.2739">Green et al 2010</a>, <a class="bibr" href="#cebpa-aml.REF.fasan.2014.794" rid="cebpa-aml.REF.fasan.2014.794">Fasan et al 2014</a>].</div></li><li class="half_rhythm"><div><i>CEBPA</i> pathogenic variants have not been detected in solid tumors, although deregulation of <i>CEBPA</i> expression has been reported in liver, lung, and breast cancer, suggesting alternative mechanisms of abrogation [<a class="bibr" href="#cebpa-aml.REF.louren_o.2017.5221" rid="cebpa-aml.REF.louren_o.2017.5221">Lourenço & Coffer 2017</a>].</div></li></ul></div></div><div id="cebpa-aml.Chapter_Notes"><h2 id="_cebpa-aml_Chapter_Notes_">Chapter Notes</h2><div id="cebpa-aml.Author_History"><h3>Author History</h3><p>Jude Fitzgibbon, PhD (2016-present)<br />Roger D Klein, MD, JD; Cleveland Clinic (2010-2016)<br />Guido Marcucci, MD; Ohio State University (2010-2016)<br />Kiran Tawana, MBChB, FRCPath, PhD (2016-present)</p></div><div id="cebpa-aml.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>18 February 2021 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>28 April 2016 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>21 October 2010 (me) Review posted live</div></li><li class="half_rhythm"><div>30 December 2009 (rdk) Original submission</div></li></ul></div></div><div id="cebpa-aml.References"><h2 id="_cebpa-aml_References_">References</h2><div id="cebpa-aml.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.arber.2016.2391">Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. 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Familial CEBPA-mutated acute myeloid leukemia. <span><span class="ref-journal">Semin Hematol. </span>2017;<span class="ref-vol">54</span>:87–93.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28637622" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28637622</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.tawana.2015.1214">Tawana K, Wang J, Renneville A, Bödör C, Hills R, Loveday C, Savic A, Van Delft FW, Treleaven J, Georgiades P, Uglow E, Asou N, Uike N, Debeljak M, Jazbec J, Ancliff P, Gale R, Thomas X, Mialou V, Döhner K, Bullinger L, Mueller B, Pabst T, Stelljes M, Schlegelberger B, Wozniak E, Iqbal S, Okosun J, Araf S, Frank AK, Lauridsen FB, Porse B, Nerlov C, Owen C, Dokal I, Gribben J, Smith M, Preudhomme C, Chelala C, Cavenagh J, Fitzgibbon J. Disease evolution and outcomes in familial AML with germline CEBPA mutations. <span><span class="ref-journal">Blood. </span>2015;<span class="ref-vol">126</span>:1214–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26162409" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26162409</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.tiesmeier.2003.413">Tiesmeier J, Czwalinna A, Müller-Tidow C, Krauter J, Serve H, Heil G, Ganser A, Verbeek W. Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia. <span><span class="ref-journal">Br J Haematol. </span>2003;<span class="ref-vol">123</span>:413–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14616999" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14616999</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.xiao.2011.5257">Xiao H, Shi J, Luo Y, Tan Y, He J, Xie W, Zhang L, Wang Y, Liu L, Wu K, Yu X, Cai Z, Lin M, Ye X, Huang H. First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. <span><span class="ref-journal">Blood. </span>2011;<span class="ref-vol">117</span>:5257–60.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21403128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21403128</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.yan.2016.652">Yan B, Ng C, Moshi G, Ban K, Lee PL, Seah E, Chiu L, Koay ES, Liu TC, Ng CH, Chng WJ, Koh LP. Myelodysplastic features in a patient with germline CEBPA-mutant acute myeloid leukaemia. <span><span class="ref-journal">J Clin Pathol. </span>2016;<span class="ref-vol">69</span>:652–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27010436" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27010436</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="cebpa-aml.REF.ye.2013.385">Ye M, Zhang H, Amabile G, Yang H, Staber PB, Zhang P, Levantini E, Alberich-Jordà M, Zhang J, Kawasaki A, Tenen DG. C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. <span><span class="ref-journal">Nat Cell Biol. </span>2013;<span class="ref-vol">15</span>:385–94.</span> [<a href="/pmc/articles/PMC3781213/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3781213</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23502316" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23502316</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK47457_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Kiran Tawana</span>, MBChB, FRCPath, PhD<div class="affiliation small">Barts Cancer Institute
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Queen Mary University of London
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London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.shn.sekoorbnedda@anawat.narik" class="oemail">ku.shn.sekoorbnedda@anawat.narik</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Jude Fitzgibbon</span>, BA, PhD<div class="affiliation small">Barts Cancer Institute
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Queen Mary University of London
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London, United Kingdom<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ku.ca.lumq@nobbigztif.j" class="oemail">ku.ca.lumq@nobbigztif.j</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">October 21, 2010</span>; Last Update: <span itemprop="dateModified">February 18, 2021</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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hereby granted to reproduce, distribute, and translate copies of content materials for
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noncommercial research purposes only, provided that (i) credit for source (<a href="http://www.genereviews.org/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">http://www.genereviews.org/</a>) and copyright (© 1993-2025 University of
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>. No further modifications are allowed. For clarity, excerpts
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of GeneReviews chapters for use in lab reports and clinic notes are a permitted
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use.</p><p class="small">For more information, see the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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Disclaimer</a>.</p><p class="small">For questions regarding permissions or whether a specified use is allowed,
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Tawana K, Fitzgibbon J. CEBPA-Associated Familial Acute Myeloid Leukemia (AML) 2010 Oct 21 [Updated 2021 Feb 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/cdkl5-def/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/chchd10-dis/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobcebpaamlTmoleculargenetictestingus"><div id="cebpa-aml.T.molecular_genetic_testing_us" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in <i>CEBPA</i>-Associated Familial Acute Myeloid Leukemia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47457/table/cebpa-aml.T.molecular_genetic_testing_us/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cebpa-aml.T.molecular_genetic_testing_us_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CEBPA</i>
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</td><td headers="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% (14/14 families) <sup>4, 5</sup></td></tr><tr><td headers="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>6</sup></td><td headers="hd_h_cebpa-aml.T.molecular_genetic_testing_us_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cebpa-aml.TF.1.1"><p class="no_margin">See <a href="/books/NBK47457/?report=reader#cebpa-aml.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="cebpa-aml.TF.1.2"><p class="no_margin">See <a href="#cebpa-aml.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="cebpa-aml.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="cebpa-aml.TF.1.4"><p class="no_margin">Sequencing of the coding region does not detect putative partial or complete gene deletions or variants in promoter regions. To date, however, no such germline <i>CEBPA</i> variants have been reported as causative of familial AML.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="cebpa-aml.TF.1.5"><p class="no_margin"><a class="bibr" href="#cebpa-aml.REF.smith.2004.2403" rid="cebpa-aml.REF.smith.2004.2403">Smith et al [2004]</a>, <a class="bibr" href="#cebpa-aml.REF.sellick.2005.1276" rid="cebpa-aml.REF.sellick.2005.1276">Sellick et al [2005]</a>, <a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al [2008]</a>, <a class="bibr" href="#cebpa-aml.REF.renneville.2009.804" rid="cebpa-aml.REF.renneville.2009.804">Renneville et al [2009]</a>, <a class="bibr" href="#cebpa-aml.REF.nanri.2010.237" rid="cebpa-aml.REF.nanri.2010.237">Nanri et al [2010]</a>, <a class="bibr" href="#cebpa-aml.REF.stelljes.2011.1209" rid="cebpa-aml.REF.stelljes.2011.1209">Stelljes et al [2011]</a>, <a class="bibr" href="#cebpa-aml.REF.taskesen.2011.2469" rid="cebpa-aml.REF.taskesen.2011.2469">Taskesen et al [2011]</a>, <a class="bibr" href="#cebpa-aml.REF.xiao.2011.5257" rid="cebpa-aml.REF.xiao.2011.5257">Xiao et al [2011]</a>, <a class="bibr" href="#cebpa-aml.REF.debeljak.2013.e73" rid="cebpa-aml.REF.debeljak.2013.e73">Debeljak et al [2013]</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al [2015]</a>, <a class="bibr" href="#cebpa-aml.REF.pathak.2016.846" rid="cebpa-aml.REF.pathak.2016.846">Pathak et al [2016]</a>, <a class="bibr" href="#cebpa-aml.REF.yan.2016.652" rid="cebpa-aml.REF.yan.2016.652">Yan et al [2016]</a>, <a class="bibr" href="#cebpa-aml.REF.mendoza.2021.1251" rid="cebpa-aml.REF.mendoza.2021.1251">Mendoza et al [2021]</a></p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="cebpa-aml.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="cebpa-aml.TF.1.7"><p class="no_margin">No data on detection rate of gene-targeted deletion/duplication analysis are available.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcebpaamlTrecommendedevaluationsfoll"><div id="cebpa-aml.T.recommended_evaluations_foll" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with <i>CEBPA</i>-Associated Familial Acute Myeloid Leukemia</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47457/table/cebpa-aml.T.recommended_evaluations_foll/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cebpa-aml.T.recommended_evaluations_foll_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>AYA/pediatric</b>
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<br />
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<b>AML</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Management of younger persons to be directed by relevant specialist teams (e.g., AYA or pediatric hematologists)</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>AML /</b>
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<br />
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<b>Assessment</b>
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<br />
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<b>for suitable</b>
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<br />
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<b>HSCT donor</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">HLA typing & virology tests (hepatitis A, B, C, & HIV)</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><i>CEBPA</i> site-specific testing of family members at risk using either of the following:
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<ul><li class="half_rhythm"><div>Buccal, salivary, or skin DNA</div></li><li class="half_rhythm"><div>Peripheral blood DNA in persons w/no history of preceding hematologic disease & normal CBC</div></li></ul>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Family members w/o an inherited <i>CEBPA</i> pathogenic variant may be offered HLA typing to assess their compatibility for stem cell donation to their affected relative.</td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Fertility</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Provide info re oocyte & sperm cryopreservation to persons of childbearing potential</div></li><li class="half_rhythm"><div>Women: negative pregnancy test prior to commencing therapy</div></li></ul>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>CNS AML</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LP if symptoms suggest CNS disease.</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The timing of LP in AML is controversial.</td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Treatment-</b>
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<br />
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<b>related heart</b>
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<br />
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<b>disease</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac scan in persons w/personal history of (or signs & symptoms suspicious for) heart disease & in those who have received previous anthracycline therapy</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic</b>
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<br />
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<b>counseling</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>By genetics professionals <sup>1</sup></div></li><li class="half_rhythm"><div>Obtain a detailed family history & identify relatives who are obligate heterozygotes or potential heterozygotes for a <i>CEBPA</i> pathogenic variant & thus at risk for <i>CEBPA</i>-assoc familial AML.</div></li></ul>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons & their families re nature, MOI, & implications of <i>CEBPA</i>-assoc familial AML in facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support/</b>
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<br />
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<b>resources</b>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess:
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<ul><li class="half_rhythm"><div>Use of community or <a href="#cebpa-aml.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a>;</div></li><li class="half_rhythm"><div>Need for social work involvement for parental support;</div></li><li class="half_rhythm"><div>Need for home nursing referral.</div></li></ul>
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</td><td headers="hd_h_cebpa-aml.T.recommended_evaluations_foll_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AYA = adolescent and young adult; AML = acute myeloid leukemia; CBC = complete blood count; CNS = central nervous system; HLA = human leukocyte antigen; HSCT = hematopoietic stem cell transplantation; LP = lumbar puncture; MOI = mode of inheritance</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="cebpa-aml.TF.2.1"><p class="no_margin">Medical geneticist, certified genetic counselor, or certified advanced genetic nurse</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcebpaamlmolgenTA"><div id="cebpa-aml.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>CEBPA-Associated Familial Acute Myeloid Leukemia (AML): Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47457/table/cebpa-aml.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cebpa-aml.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_cebpa-aml.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_cebpa-aml.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_cebpa-aml.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_cebpa-aml.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_cebpa-aml.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_cebpa-aml.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/1050" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>CEBPA</i>
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</a>
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</td><td headers="hd_b_cebpa-aml.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=1050" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">19q13<wbr style="display:inline-block"></wbr>​.11</a>
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</td><td headers="hd_b_cebpa-aml.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P49715" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CCAAT/enhancer-binding protein alpha</a>
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</td><td headers="hd_b_cebpa-aml.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CEBPA" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CEBPA</a>
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</td><td headers="hd_b_cebpa-aml.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=CEBPA[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">CEBPA</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="cebpa-aml.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobcebpaamlmolgenTB"><div id="cebpa-aml.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for CEBPA-Associated Familial Acute Myeloid Leukemia (AML) (<a href="/omim/116897,601626" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47457/table/cebpa-aml.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cebpa-aml.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/116897" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">116897</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CCAAT/ENHANCER-BINDING PROTEIN, ALPHA; CEBPA</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/601626" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">601626</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LEUKEMIA, ACUTE MYELOID; AML</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobcebpaamlTnotablefamilialacutemyelo"><div id="cebpa-aml.T.notable_familial_acute_myelo" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Notable Familial Acute Myeloid Leukemia-Associated <i>CEBPA</i> Germline Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47457/table/cebpa-aml.T.notable_familial_acute_myelo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__cebpa-aml.T.notable_familial_acute_myelo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference</th></tr></thead><tbody><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_1" rowspan="9" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004364.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_004364<wbr style="display:inline-block"></wbr>​.5</a>
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<br />
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<p>
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_004355.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_004355<wbr style="display:inline-block"></wbr>​.2</a>
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</p>
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</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.68delC</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Pro23ArgfsTer137</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.smith.2004.2403" rid="cebpa-aml.REF.smith.2004.2403">Smith et al [2004]</a>
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</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.68dupC</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.His24AlafsTer84</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a class="bibr" href="#cebpa-aml.REF.sellick.2005.1276" rid="cebpa-aml.REF.sellick.2005.1276">Sellick et al [2005]</a>, <a class="bibr" href="#cebpa-aml.REF.renneville.2009.804" rid="cebpa-aml.REF.renneville.2009.804">Renneville et al [2009]</a>, <a class="bibr" href="#cebpa-aml.REF.tawana.2015.1214" rid="cebpa-aml.REF.tawana.2015.1214">Tawana et al [2015]</a></td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.141delC</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ala48ProfsTer112</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al [2008]</a>
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</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.147_165del19</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu50AlafsTer104</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.debeljak.2013.e73" rid="cebpa-aml.REF.debeljak.2013.e73">Debeljak et al [2013]</a>
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</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.158delG</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly53AlafsTer107</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.taskesen.2011.2469" rid="cebpa-aml.REF.taskesen.2011.2469">Taskesen et al [2011]</a>
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</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.189delC</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Asp63GlufsTer97</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.314_315insT</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe106LeufsTer2</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.pabst.2008.5088" rid="cebpa-aml.REF.pabst.2008.5088">Pabst et al [2008]</a>
|
|
</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.932A>C</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln311Pro</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.pathak.2016.846" rid="cebpa-aml.REF.pathak.2016.846">Pathak et al [2016]</a>
|
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</td></tr><tr><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.442G>T</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu148Ter</td><td headers="hd_h_cebpa-aml.T.notable_familial_acute_myelo_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a class="bibr" href="#cebpa-aml.REF.mendoza.2021.1251" rid="cebpa-aml.REF.mendoza.2021.1251">Mendoza et al [2021]</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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