CEBPA-Associated Familial Acute Myeloid Leukemia (PDQ®): Genetics - Health Professional Information [NCI]

Introduction and Clinical Manifestations of CEBPA-Associated Familial Acute Myeloid Leukemia (AML)

The CEBPAgene is a granulocytic transcription factor (C/EBPα) that serves an important role in myeloid cell differentiation. Somatic mutations in CEBPA occur in approximately 10% to 15% of all AML cases. The presence of two somatic mutations in CEBPA (also known as CEBPAdm) is recognized as a unique clinical entity associated with favorable outcomes, even in the event of relapse.[1] Germline pathogenic variants in CEBPA were reported in 2004 in a family with hereditary, nonsyndromic AML.[2]CEBPA-associated familial AML (also known as familial AML with a CEBPAvariant) became the second autosomal dominant AML predisposition syndrome described (RUNX1-familial platelet disorder was the first).[3]

Features of CEBPA-associated familial AML include the following:

• Highly penetrant: Unlike several other myelodysplastic syndromes (MDS)/AML predisposition syndromes, germline CEBPA pathogenic variants appear to be highly penetrant, conferring greater than a 90% lifetime risk to develop AML.[4,5,6]
• Early-onset AML: Germline CEBPA pathogenic variants are associated with early-onset AML that can occur in childhood.[7] Published research on families with CEBPA germline pathogenic variants have reported that AML onset can occur between the ages of 1.75 to 46 years.
• De novo AML: Inherited CEBPA pathogenic variants can predispose individuals to de novo AML without prior prolonged antecedent cytopenias or multilineage dysplasia.[2]
• AML similar to somatic CEBPA variant(s): The characteristics of AML arising from a germline CEBPA pathogenic variant are strikingly similar to the characteristics seen in patients with somatic CEBPA mutation(s). These include the following: normal cytogenetics, French-American-British (FAB) AML subtypes M1 and M2, numerous Auer rods seen in peripheral blood and bone marrow blasts, and aberrant CD7 expression detected by flow cytometry.[8]

References:

1. Taskesen E, Bullinger L, Corbacioglu A, et al.: 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 117 (8): 2469-75, 2011.
2. Smith ML, Cavenagh JD, Lister TA, et al.: Mutation of CEBPA in familial acute myeloid leukemia. N Engl J Med 351 (23): 2403-7, 2004.
3. Johns Hopkins University: Online Mendelian Inheritance in Man: CCAAT/Enhancer-Binding Protein, Alpha; CEBPA. Johns Hopkins University, 2022. Available online. Last accessed October 9, 2023.
4. Owen C, Barnett M, Fitzgibbon J: Familial myelodysplasia and acute myeloid leukaemia--a review. Br J Haematol 140 (2): 123-32, 2008.
5. Pabst T, Eyholzer M, Fos J, et al.: Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 100 (8): 1343-6, 2009.
6. Renneville A, Roumier C, Biggio V, et al.: Cooperating gene mutations in acute myeloid leukemia: a review of the literature. Leukemia 22 (5): 915-31, 2008.
7. Tawana K, Wang J, Renneville A, et al.: Disease evolution and outcomes in familial AML with germline CEBPA mutations. Blood 126 (10): 1214-23, 2015.
8. Nickels EM, Soodalter J, Churpek JE, et al.: Recognizing familial myeloid leukemia in adults. Ther Adv Hematol 4 (4): 254-69, 2013.

Genetics and Molecular Biology of CEBPA-Associated Familial Acute Myeloid Leukemia (AML)

The CEBPA gene is located on chromosome 19q13.1. Leukemia arising from an inherited germline CEBPApathogenic variant follows a two-hit mechanism of leukemogenesis. Germline CEBPA pathogenic variants cluster in the N-terminus (5' end) of the CEBPAgene. The second somatic variant (at the C-terminus; 3' end) is acquired on the other CEBPAallele (in trans) when leukemia develops.[1,2] Interestingly, while the same germline pathogenic variants are present in multiple family members, individuals within families acquire distinct somatic variants in the C-terminus region of CEBPA. In some cases, more than one C-terminus variant can be acquired, suggesting two distinct episodes of AML in one individual.[3] Patients with CEBPA germline pathogenic variants often acquire GATA2 somatic variants when they develop AML.[4]

The prevalence of CEBPA-associated familial AML, like that of many other inherited AML predisposition syndromes, is unknown. However, germline CEBPA pathogenic variants may account for up to 1% of all AML cases, as extrapolated from somatic testing data.[5,6] In one series, 2 of 18 patients (11%) with AML and a somatic CEBPA variant (also called CEBPA-mutated AML) were found to carry germline pathogenic variants in the N-terminus of CEBPA.[7] In a second study, 5 of 71 patients (7%) with CEBPA-mutated AML carried a CEBPA germline pathogenic variant, suggesting that approximately 10% of individuals with biallelic CEBPA-mutated AML harbor germline pathogenic variants in CEBPA.[8] Therefore, genetic testing for CEBPA germline pathogenic variants is indicated in any patient who presents with AML and CEBPA somatic variants (particularly biallelic CEBPA somatic variants).

References:

1. Leroy H, Roumier C, Huyghe P, et al.: CEBPA point mutations in hematological malignancies. Leukemia 19 (3): 329-34, 2005.
2. Kraft IL, Godley LA: Identifying potential germline variants from sequencing hematopoietic malignancies. Blood 136 (22): 2498-2506, 2020.
3. Sellick GS, Spendlove HE, Catovsky D, et al.: Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia. Leukemia 19 (7): 1276-8, 2005.
4. Green CL, Tawana K, Hills RK, et al.: GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations. Br J Haematol 161 (5): 701-705, 2013.
5. Pabst T, Eyholzer M, Fos J, et al.: Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer 100 (8): 1343-6, 2009.
6. Preudhomme C, Sagot C, Boissel N, et al.: Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100 (8): 2717-23, 2002.
7. Pabst T, Eyholzer M, Haefliger S, et al.: Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia. J Clin Oncol 26 (31): 5088-93, 2008.
8. Taskesen E, Bullinger L, Corbacioglu A, et al.: 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 117 (8): 2469-75, 2011.

Management and Prognosis for CEBPA-Associated Familial Acute Myeloid Leukemia (AML)

CEBPA-associated familial AML is similar to sporadic AML with somatic biallelic CEBPAvariants in that both often have a favorable prognosis and preclude the need for hematopoietic stem cell transplant (HSCT). However, in individuals with AML arising from a germline CEBPApathogenic variant, the HSCT's purpose is to both treat the AML and to replace the constitutional stem cell population that harbors the AML susceptibility.[1] Like in all inherited predispositions to AML, great care needs to be taken to avoid use of a stem cell donor who carries a germline CEBPA pathogenic variant. Donor-derived leukemia has been reported in individuals with CEBPA-associated familial AML who received a transplant, unknowingly, from a donor who carried a CEBPA germline pathogenic variant.[2]

References:

1. Stelljes M, Corbacioglu A, Schlenk RF, et al.: 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 25 (7): 1209-10, 2011.
2. Xiao H, Shi J, Luo Y, et al.: First report of multiple CEBPA mutations contributing to donor origin of leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood 117 (19): 5257-60, 2011.

Latest Updates to This Summary (11 / 25 / 2024)

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Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about CEBPA-associated familial AML. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for CEBPA-Associated Familial Acute Myeloid Leukemia are:

• Julia Cooper, MS, CGC (Ohio State University)
• Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
• Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

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PDQ® Cancer Genetics Editorial Board. PDQ CEBPA-Associated Familial Acute Myeloid Leukemia. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/publications/pdq/information-summaries/genetics/cebpa-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 38113348]

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Last Revised: 2024-11-25