NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

CEBPA-Associated Familial Acute Myeloid Leukemia (AML)

Synonym: CEBPA-Dependent Familial Acute Myeloid Leukemia

, MBChB, FRCPath and , BA, PhD.

Author Information

Initial Posting: ; Last Update: April 28, 2016.

Estimated reading time: 20 minutes


Clinical characteristics.

CEBPA-associated familial acute myeloid leukemia (AML) is defined as AML in which a heterozygous germline CEBPA pathogenic variant is present in a family in which multiple individuals have 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. Too few individuals with CEBPA-associated familial AML have been reported to be certain about the natural history of the disease. 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 older than age 45 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 due to preexisting clones.


The diagnosis of CEBPA-associated familial AML is established by identification of a heterozygous germline CEBPA pathogenic variant in a specimen that contains only non-leukemic cells from an individual with AML, or by observing segregation of a shared germline CEBPA pathogenic variant across affected family members.


Treatment of manifestations: Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy. Hematopoietic stem cell transplantation (HSCT) from a volunteer unrelated donor (VUD) 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.

Prevention of secondary complications: Similar to that for other types of AML (i.e., administration of blood products such as red blood cell and platelet transfusions as needed; treatment of infections with antibiotics; and use of prophylactic antibiotics and anti-fungal agents during periods of severe neutropenia).

Surveillance: Similar to that for other forms of AML. Because of the increased risk of leukemia recurrence in persons with familial AML, lifelong surveillance may be warranted.

Genetic counseling.

Predisposition to CEBPA-associated familial AML is inherited in an autosomal dominant manner. Most individuals diagnosed with CEBPA-associated familial AML have had an affected parent who shares the germline pathogenic variant. Germline CEBPA 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 diagnosis for pregnancies at increased risk is possible if the germline CEBPA pathogenic variant in the family is known.


To date there are no universally accepted guidelines for the detection of germline pathogenic variants associated with acute myeloid leukemia (AML), although a useful algorithm has been proposed by Nickels et al [2013].

Suggestive Findings

CEBPA-associated familial AML should be suspected in individuals with the following clinical and supportive laboratory findings:

Clinical findings

  • Individuals with AML who also have a family history of AML
  • Individuals who have developed AML at an early age (<50 years)

Supportive laboratory findings

  • Young individuals with AML whose leukemic cells have a pathogenic variant in both copies of CEBPA
  • Normal karyotype in leukemic cells
  • A preponderance of French-American-British (FAB) Cooperative Group AML Classification subtypes M1 or M2 as established by morphologic analysis of peripheral blood or bone marrow blasts
  • 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)
  • Aberrant CD7 expression on blasts as demonstrated by flow cytometry

Note: A provisional diagnostic category of "AML with mutated CEBPA" was proposed in the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues [Arber et al 2008]. This classification is primarily intended for sporadic AML and does not distinguish familial forms of disease or the presence of a pathogenic variant in one or both copies of CEBPA; only the latter have favorable prognostic significance in AML.

For this GeneReview, the following definitions are used:

CEBPA-associated familial AML is defined by the presence of a germline CEBPA pathogenic variant. Germline variants may be inherited across multiple generations or develop de novo in parental germ cells, prior to their transmission. Once inherited, they are present in every cell of an individual as part of their unique genetic make-up. Germline CEBPA pathogenic variants typically coincide with a family history of AML and the diagnosis is established by either of the following:

Sporadic CEBPA-associated AML is defined as AML in which a somatic CEBPA pathogenic variant(s) is acquired in leukemic cells alone; these variants are absent in all of the individual's non-leukemic cells (see Molecular Genetics).

Establishing the Diagnosis

The diagnosis of CEBPA-associated familial AML is established in a proband with a confirmed germline CEBPA pathogenic variant (see Table 1). Because CEBPA-associated familial AML develops from cells that have a pathogenic (cancer-predisposing) variant in both copies of CEBPA, leukemic cells frequently demonstrate both a germline and a somatic CEBPA variant at AML diagnosis. The germline pathogenic variant is typically a frameshift located in the CEBPA region encoding the N-terminal C/EBPα protein, while the second somatic pathogenic variant acquired in leukemic cells is typically in the region encoding the C-terminal (see Molecular Genetics).

Note: In the literature, the terms CEBPAdm and CEBPAsm may be used. These terms refer to leukemic cells with a pathogenic variant in both copies of CEBPA ("double mutation") or in only one copy of CEBPA ("single mutation"). These terms alone do not specify if the pathogenic variant is germline or somatic (see Molecular Genetic Pathogenesis).

Molecular testing approaches include single-gene testing and use of a multigene panel:

  • Single-gene testing. Sequence analysis of CEBPA is performed in a non-leukemic specimen.
    Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active AML. Testing a non-involved specimen, such as cells obtained by buccal swab/saliva, skin biopsy or cultured dendritic cells, is imperative. (2) It should be noted that CEBPA pathogenic variants are found in the leukemic cells of approximately 9% of persons with AML, including 15%-18% of persons with normal-karyotype AML [Arber et al 2008, Renneville et al 2008]. However, few of these individuals have a germline CEBPA pathogenic variant. (3) Testing of blood or bone marrow during complete remission from AML may also be performed to detect germline variants. The percentage of residual leukemic cells in remission samples is negligible, ensuring that somatic variants are not falsely classified as germline variants.
  • A multigene panel that includes CEBPA and other genes of interest (see Differential Diagnosis) may also be considered. 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 GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost 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.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in CEBPA-Associated Familial Acute Myeloid Leukemia

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
CEBPASequence analysis 3100% (11/11 families) 4, 5
Gene-targeted deletion/duplication analysis 6Unknown 7

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. 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 here.


Sequencing of the coding region does not detect putative partial or complete gene deletions or variants in promoter regions. However, no such germline variants causing familial AML with mutated CEBPA have been reported to date.


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.


No data on detection rate of gene-targeted deletion/duplication analysis are available.

Clinical Characteristics

Clinical Description

Germline CEBPA pathogenic variants were first associated with the autosomal dominant transmission of acute myeloid leukemia (AML) in 2004 [Smith et al 2004]. Over the last decade, more than ten families have been reported, all manifesting a highly penetrant AML phenotype as described above. Given the limited number of individuals described in the literature, it is possible that the true range of clinical phenotypes may vary [Pabst & Mueller 2009] and ongoing investigation of this syndrome is essential.

The age of onset of CEBPA-associated familial AML is variable, but appears to be earlier than sporadic AML. Disease onset has been reported in persons as young as 1.8 years [Debeljak et al 2013] and older than 45 years [Pabst et al 2008]. By contrast, the median age at diagnosis of persons with sporadic AML is 65 years.

From an analysis of ten pedigrees with CEBPA-associated familial AML, the disease follows a course similar to sporadic AML with CEBPA pathogenic variants in both copies (CEBPAdm). The prognosis of individuals with familial AML appears to be favorable, with ten-year overall survival (OS) reaching 67%, compared to 54% OS of younger adults with sporadic AML associated with two CEBPA pathogenic variants and 29% OS with sporadic AML associated with a single CEBPA pathogenic variant [Tawana et al 2015].

Individuals with CEBPA-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 CEBPA pathogenic variant from that observed in the original tumor clone. This phenomenon contrasts with relapse in individuals with sporadic AML, where CEBPA pathogenic variants are stable throughout the disease course [Tiesmeier et al 2003, Shih et al 2006, Hollink et al 2011].

Genotype-Phenotype Correlations

To date, the majority of germline CEBPA pathogenic variants are frameshift variants located in the N-terminal of the gene (preceding the internal start codon). Individuals commonly present with AML (of FAB subtypes M1, M2 or M4) following the acquisition of somatic CEBPA (and additional) pathogenic variants.


Analysis of pedigrees reported to date suggests that germline CEBPA pathogenic variants exhibit high penetrance for the development of AML [Nickels et al 2013, Tawana et al 2015]. The penetrance of pathogenic variants may vary within and between families; data from ten families with germline CEBPA pathogenic variants revealed that more than 80% of confirmed or presumed obligate adult heterozygotes have developed disease to date [Tawana et al 2015].


CEBPA-associated familial AML is very rare, with only eleven pedigrees reported as of this writing [Smith et al 2004, Sellick et al 2005, Pabst et al 2008, Renneville et al 2009, Nanri et al 2010, Stelljes et al 2011, Taskesen et al 2011, Xiao et al 2011, Debeljak et al 2013, Tawana et al 2015].

It has been suggested that 5%-10% of individuals with presumed sporadic CEBPA-associated AML, may have a germline CEBPA pathogenic variant. Pabst et al [2008] reported that two of 18 individuals (11%) with CEBPA-associated AML had a germline CEBPA pathogenic variant and a family history of AML. A larger series reported by Taskesen et al [2011] identified a germline CEBPA pathogenic variant in five of 71 individuals (7%); two of the five had a family history of AML.

Differential Diagnosis

The differential diagnosis for CEBPA-associated familial acute myeloid leukemia (AML) includes:

  • Sporadic AML with somatic mutation of CEBPA
  • AML secondary to environmental exposures (e.g., benzene, radiation, chemotherapy)
  • Sporadic AML with more than one affected family member
    Note: The more affected individuals in a family (and the closer the relationships) the greater the likelihood of a common cause.

Note: AML is a relatively rare disease (~13,300 cases/year in the US); therefore, pedigrees with more than one individual with AML could have a heritable predisposition or a common exposure [Owen et al 2008].


Evaluations Following Initial Diagnosis of CEBPA-Associated Familial AML

To establish the extent of disease and needs of an individual newly diagnosed with AML, the following evaluations are recommended:

  • Cardiac scan in individuals with a personal history of – or signs and symptoms suspicious for – heart disease and in those who have received previous anthracycline therapy
  • HLA typing in anticipation of hematopoietic stem cell transplantation (HSCT)
  • Lumbar puncture (LP) if symptoms suggest central nervous system disease. The timing of LP in AML is controversial.
  • Consultation with a clinical geneticist and/or genetic counselor

Evaluation of an individual with a confirmed diagnosis of CEBPA-associated familial AML should include:

  • Assembly of a detailed pedigree to identify additional affected individuals and potential carriers of the inherited pathogenic variant;
  • Recommendation of consultation with a genetic counselor for all at-risk family members;
  • Molecular testing of family members at risk using buccal, salivary or skin DNA. Peripheral blood DNA may also be used in individuals with no history of preceding hematologic disease and normal complete blood count (CBC).
    • Comprehensive evaluation and screening of family members enables improved characterization of the clinical manifestations and penetrance within the pedigree.
    • Family members without the inherited pathogenic variant may be offered human leukocyte antigen (HLA) typing to assess their compatibility for stem cell donation to their affected relative.

Note: In all familial leukemia syndromes with a known inherited pathogenic variant, it is essential that screening of the pathogenic variant be performed in all relatives at risk prior to consideration of stem cell donation.

Treatment of Manifestations

Management of CEBPA-associated familial AML does not differ from that of sporadic CEBPA-associated AML [National Comprehensive Cancer Network 2009, Döhner et al 2010].

Treatment usually includes cytarabine/anthracycline-based induction and cytarabine-based consolidation chemotherapy with or without HSCT according to clinical, cytogenetic, and molecular risk. For younger individuals with AML (even those without a clear family history), there is now increasing awareness that germline variants should be investigated and excluded prior to consideration of HSCT using sib/related donors. 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.

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).

Prevention of Secondary Complications

Prevention of secondary complications is similar to that for other types of AML:

  • Supportive care includes blood products such as red blood cell and platelet transfusions as needed and treatment of infections with antibiotics.
  • Prophylactic antibiotics and antifungal agents are administered during periods of severe neutropenia including the consolidation and post-transplantation periods [National Comprehensive Cancer Network 2009].


Affected individuals. Surveillance for CEBPA-associated familial AML is similar to that for other forms of AML. There are no generally accepted minimal residual disease (MRD) markers in CEBPA-associated AML or in most other AML subtypes with normal karyotypes.

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:

  • 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;
  • Bone marrow aspiration when cytopenia and/or an abnormal peripheral blood smear are present.

Note: The use of flow cytometry for MRD monitoring is controversial.

Individuals with a germline CEBPA 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) [Pabst et al 2009, Tawana et al 2015]. In light of these data, lifelong clinical surveillance is warranted to ensure prompt recognition and appropriate management of disease recurrence. Repeat testing of CEBPA at recurrence is important to help distinguish conventional relapse from new, independent leukemic episodes.

Asymptomatic carriers. Asymptomatic individuals with a pathogenic CEBPA germline variant may be reviewed with CBC profiling every six to 12 months. Bone marrow examination may be performed if there is an appropriate clinical indication (e.g., abnormalities in CBC). Referral for post-testing genetic counseling should be considered as appropriate.

Agents/Circumstances to Avoid

Use of sib or related donors for HSCT without prior assessment of the pathogenic germline variant in these individuals.

Evaluation of Relatives at Risk

To date, all individuals with germline pathogenic CEBPA variants have presented with overt AML without any preceding blood count abnormalities or myelodysplasia, this in contrast with other familial leukemia syndromes such as those associated with germline RUNX1 or GATA2 pathogenic variants [Nickels et al 2013].

The decision to test for an inherited pathogenic variant is ultimately governed by personal choice, the reassurance of regular clinical follow up, and provision of genetic counseling. It is noteworthy that 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), providing further rationale for molecular evaluation of at-risk relatives. There are currently no preemptive treatments available for asymptomatic carriers of a germline CEBPA pathogenic variant.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search Clinical 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Predisposition to CEBPA-associated familial acute myeloid leukemia (AML) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with CEBPA-associated familial AML have had an affected parent who shares the germline pathogenic variant.
  • In rare cases, a proband may have a de novo germline CEBPA pathogenic variant.
  • Recommendations for the evaluation of apparently asymptomatic parents of a proband with a germline pathogenic variant include a complete blood count (CBC) with hematologic indices, peripheral blood smear, and testing for the germline CEBPA pathogenic variant identified in the proband.
  • The family history of some individuals diagnosed with CEBPA-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 confirmed until appropriate evaluations have been performed.
  • Note: If the parent is the individual in whom the germline pathogenic variant first occurred s/he could potentially have somatic mosaicism for the germline variant.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband’s parents:

Offspring of a proband. Each child of an individual with CEBPA-associated familial AML has a 50% chance of inheriting the germline pathogenic variant.

Other family members. The risk of other family members inheriting the germline CEBPA pathogenic variant depends on the status of the proband's parents: if a parent is affected and/or has the germline pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. If neither parent of a proband with CEBPA-associated familial AML has the pathogenic variant or clinical evidence of AML, the CEBPA pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Testing of at-risk asymptomatic family members. If a germline CEBPA 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 Evaluation of Relatives at Risk).

Family planning

  • The optimal time for determination of genetic risk in offspring of persons with known CEBPA-associated familial AML is before pregnancy. Because CEBPA-associated familial AML is rare, general screening of individuals with AML or a family history of AML for a CEBPA germline pathogenic variant is not recommended for family planning purposes unless CEBPA-associated familial AML is suspected.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

In AML generally, tissue banking that is performed for future research purposes should include banking of DNA, RNA, protein lysates, and cryopreserved cells.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once a germline CEBPA pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic diagnosis for a pregnancy at increased risk for CEBPA-associated familial AML are possible options.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

CEBPA-Associated Familial Acute Myeloid Leukemia (AML): Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for CEBPA-Associated Familial Acute Myeloid Leukemia (AML) (View All in OMIM)


Molecular Genetic Pathogenesis

CEBPA 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 [Koschmieder et al 2009]. The role of mutation of CEBPA 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 mutations [Kirstetter et al 2008], combined N- and C- terminal mutations [Bereshchenko et al 2009], or conditional loss of C/EBPα [Ye et al 2013].

Note: The terms CEBPAdm and CEBPAsm are used in the literature and refer to leukemic cells with a pathogenic variant in both ("double mutation") or in a single copy of CEBPA ("single mutation"), respectively. These terms do not indicate the location of variants within the gene or whether they are germline or somatic. As mentioned previously, the latter distinction is based upon the identification of pathogenic variants in non-leukemic DNA. In individuals with sporadic AML (caused by the somatic acquisition of CEBPA pathogenic variants), double and single mutated subtypes occur with approximately equal frequency. Notably, only double CEBPA mutations (predominantly combining N-terminal frameshift and C-terminal in-frame insertions or deletions) are associated with favorable prognostic significance [Dufour et al 2010, Green et al 2010].

Gene structure. CEBPA is a single-exon gene; the primary CEBPA transcript (NM_004364.4) is 2631 bp. Initiation of translation at two in-frame AUG start codons (nucleotides 151-153 and 508-51) results in two C/EBPα protein isoforms. For a detailed summary of gene and protein information, see Table A, Gene.

Benign germline variants. A few benign variants in the CEBPA coding region have been reported (see Table 2).

Pathogenic germline variants. All reported pathogenic germline variants are small deletions, duplications, or insertions resulting in a frameshift causing premature truncation at the N-terminal region of the C/EBPα protein. The analytic sensitivity of sequence analysis is expected to be >99% for variants within the coding region. The germline variants identified to date are listed in Table 2; the c.217_218insC variant has been reported in two pedigrees. Thus far, reported germline variants have been small insertions/deletions that result in frameshifts in CEBPA regions that encode the N-terminal region of the protein and predict premature termination of synthesis of the full-length C/EBPα protein (see Normal gene product).

Table 2.

Selected CEBPA Germline Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
c.690G>Tp.Thr230= 2
c.217_218insC 3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Variant designation that does not conform to current naming conventions


Indicates that no effect on protein level is expected


Reported in two pedigrees

Normal gene product. The use of alternative in-frame non-AUG (GUG) and AUG start codons results in protein isoforms with different lengths (see Table A, Gene). When translation initiates from the AUG at nucleotides 151-153, isoform a (also known as C/EBP-42) is produced; it is a 42-kd transcription factor of 358 amino acids NP_004355.2. The full-length 42-kd protein contains two distinct N-terminal transactivation domains (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 of 239 amino acids that lacks the first transactivation domain and impairs interaction with the transcriptional apparatus (NP_001272758.1) is produced. The C-terminal domains are intact [Pabst & Mueller 2007, Pabst & Mueller 2009]. Evidence from cell culture identified C/EBPα protein as a tumor suppressor and an inhibitor of cell proliferation. Evidence from mouse models is consistent with the tumor suppressor activity being in the 42-kd isoform and transformation in the absence of 42 kd is mediated by a 30-kd isoform which has a dominant-negative effect leading to the formation of progenitors prone to deregulated proliferation and transformation [abstracted from Pabst & Mueller 2009].

Abnormal gene product. The reported germline pathogenic variants in CEBPA (Table 2) occur before codon 120 and cause/predict premature termination of synthesis of the full-length C/EBPα protein, with preservation of the 30-kd isoform. The 30-kd protein is believed to inhibit the action of the normal 42-kd protein encoded by the remaining normal allele in a dominant-negative manner.

Somatic CEBPA pathogenic variants

  • In CEBPA-associated familial AML. The leukemic cells of most individuals with CEBPA-associated familial AML are compound heterozygous. In addition to the germline pathogenic variant described above in the N-terminal region (see Pathogenic germline variants), 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 [Pabst & Mueller 2007, Pabst & Mueller 2009].
  • In sporadic CEBPA-associated AML. This is defined as AML in which a somatic CEBPA pathogenic variant(s) is acquired in leukemic cells alone and not in the germline. In 45%-55% of all persons with sporadic CEBPA-associated AML, two pathogenic CEBPA variants are detected (CEBPAdm); most frequently, a frameshift N-terminal variant is combined with a C-terminal in-frame insertion or deletion [Green et al 2010, Fasan et al 2014].


Literature Cited

  • Arber DA, Brunning RD, Le Beau MM, Falini B, Vardiman JW, Porwit A, Thiele J, Bloomfield CD. Acute myeloid leukaemia with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 ed. Lyon, France: WHO Press; 2008:110-23.
  • Bereshchenko O, Mancini E, Moore S, Bilbao D, Månsson R, Luc S, Grover A, Jacobsen SE, Bryder D, Nerlov C. Hematopoietic stem cell expansion precedes the generation of committed myeloid leukemia-initiating cells in C/EBPalpha mutant AML. Cancer Cell. 2009;16:390–400. [PubMed: 19878871]
  • Debeljak M, Kitanovski L, Pajič T, Jazbec J. Concordant acute myeloblastic leukemia in monozygotic twins with germline and shared somatic mutations in the gene for CCAAT-enhancer-binding protein α with 13 years difference at onset. Haematologica. 2013;98:e73–4. [PMC free article: PMC3696596] [PubMed: 23716546]
  • Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, Sierra J, Tallman MS, Löwenberg B, Bloomfield CD. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74. [PubMed: 19880497]
  • Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E, Benthaus T, Sauerland MC, Berdel WE, Büchner T, Wörmann B, Braess J, Hiddemann W, Bohlander SK, Spiekermann K. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28:570–7. [PubMed: 20038735]
  • Fasan A, Haferlach C, Alpermann T, Jeromin S, Grossmann V, Eder C, Weissmann S, Dicker F, Kohlmann A, Schindela S, Kern W, Haferlach T, Schnittger S. The role of different genetic subtypes of CEBPA mutated AML. Leukemia. 2014;28:794–803. [PubMed: 24056881]
  • Green CL, Koo KK, Hills RK, Burnett AK, Linch DC, Gale RE. Prognostic Significance of CEBPA Mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations. J Clin Oncol. 2010;28:2739–47. [PubMed: 20439648]
  • Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, Balgobind BV, Sonneveld E, Kaspers GJ, de Bont ES, Trka J, Baruchel A, Creutzig U, Pieters R, Reinhardt D, Zwaan CM. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011;96:384–92. [PMC free article: PMC3046269] [PubMed: 21134981]
  • Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Mönch K, Månsson R, Pedersen TA, Pabst T, Schrock E, Porse BT, Jacobsen SE, Bertone P, Tenen DG, Nerlov C. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13:299–310. [PubMed: 18394553]
  • Koschmieder S, Balazs H, Levantini E, Tenen DG. Dysregulation of the C/EBPα differentiation pathway in human cancer. J Clin Oncol. 2009;27:619–28. [PMC free article: PMC2645860] [PubMed: 19075268]
  • Nanri T, Uike N, Kawakita T, Iwanaga E, Hoshino K, Mitsuya H, Asou N. A family harboring a germ-line N-terminal C/EBPα mutation and development of acute myeloblastic leukemia with an additional somatic C-terminal C/EBPα mutation. Genes Chromosomes Cancer. 2010;49:237–41. [PubMed: 19953636]
  • National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology™. Available online. 2009. Accessed 4-26-13.
  • Nickels EM, Soodalter J, Churpek JE, Godley LA. Recognizing familial myeloid leukemia in adults. Ther Adv Hematol. 2013;4:254–69. [PMC free article: PMC3734901] [PubMed: 23926458]
  • Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukemia--a review. Br J Haematol. 2008;140:123–32. [PubMed: 18173751]
  • Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer. 2009;100:1343–46. [PMC free article: PMC2676545] [PubMed: 19277035]
  • Pabst T, Eyholzer M, Haefliger S, Schardt J, Mueller BU. Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol. 2008;26:5088–93. [PubMed: 18768433]
  • Pabst T, Mueller BU. Transcriptional dysregulation during myeloid transformation in AML. Oncogene. 2007;26:6829–37. [PubMed: 17934489]
  • Pabst T, Mueller BU. Complexity of CEBPA Dysregulation in Human Acute Myeloid Leukemia. Clin Cancer Res. 2009;15:5303–7. [PubMed: 19706798]
  • Renneville A, Mialou V, Philippe N, Kagialis-Girard S, Biggio V, Zabot MT, Thomas X, Bertrand Y, Preudhomme C. Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation. Leukemia. 2009;23:804–6. [PubMed: 18946494]
  • Renneville A, Roumier C, Biggio V, Nibourel O, Boissel N, Fenaux P, Preudhomme C. Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia. 2008;22:915–31. [PubMed: 18288131]
  • Sellick GS, Spendlove HE, Catovsky D, Pritchard-Jones K, Houlston RS. Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukemia. Leukemia. 2005;19:1276–8. [PubMed: 15902292]
  • Shih LY, Liang DC, Huang CF, Wu JH, Lin TL, Wang PN, Dunn P, Kuo MC, Tang TC. AML patients with CEBPalpha mutations mostly retain identical mutant patterns but frequently change in allelic distribution at relapse: a comparative analysis on paired diagnosis and relapse samples. Leukemia. 2006;20:604–9. [PubMed: 16453003]
  • Smith ML, Cavenagh JD, Lister TA, Fitzgibbon J. Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med. 2004;351:2403–7. [PubMed: 15575056]
  • Stelljes M, Corbacioglu A, Schlenk RF, Döhner K, Frühwald MC, Rossig C, Ehlert K, Silling G, Müller-Tidow C, Juergens H, Döhner H, Berdel WE, Kienast J, Koschmieder S. Allogeneic stem cell transplant to eliminate germline mutations in the gene for CCAAT-enhancer-binding protein α from hematopoietic cells in a family with AML. Leukemia. 2011;25:1209–10. [PubMed: 21455213]
  • Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, van der Poel-van de Luytgaarde SC, Damm F, Krauter J, Ganser A, Schlenk RF, Löwenberg B, Delwel R, Döhner H, Valk PJ, Döhner K. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117:2469–75. [PubMed: 21177436]
  • 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. Blood. 2015;126:1214–23. [PubMed: 26162409]
  • 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. Br J Haematol. 2003;123:413–9. [PubMed: 14616999]
  • 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. Blood. 2011;117:5257–60. [PubMed: 21403128]
  • 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. Nat Cell Biol. 2013;15:385–94. [PMC free article: PMC3781213] [PubMed: 23502316]

Chapter Notes

Author History

Jude Fitzgibbon, PhD (2016-present)
Roger D Klein, MD, JD; Cleveland Clinic (2010-2016)
Guido Marcucci, MD; Ohio State University (2010-2016)
Kiran Tawana, MBChB, FRCPath (2016-present)

Revision History

  • 28 April 2016 (sw) Comprehensive update posted live
  • 21 October 2010 (me) Review posted live
  • 30 December 2009 (rdk) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK47457PMID: 20963938


Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...