CEBPA-Associated Familial Acute Myeloid Leukemia (PDQ®)–Health Professional Version

[Note: A concerted effort is being made within the genetics community to use the term, variant rather than the term, mutation to describe genetic differences in the germline. These variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term, pathogenic variant to describe a disease-causing mutation. In this summary, the term, somatic mutations will be used to describe acquired genetic changes that arise in the hematopoietic system (blood stem cells and blood progenitor cells). For more information about variant classification, see the Cancer Genetics Overview summary.]

The CEBPA gene 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 CEBPA mutation) 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:

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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
8. Nickels EM, Soodalter J, Churpek JE, et al.: Recognizing familial myeloid leukemia in adults. Ther Adv Hematol 4 (4): 254-69, 2013. [PUBMED Abstract]

The CEBPA gene is located on chromosome 19q13.1. Leukemia arising from an inherited germline CEBPA pathogenic variant follows a two-hit mechanism of leukemogenesis. Germline CEBPA pathogenic variants cluster in the N-terminus (5’ end) of the CEBPA gene. The second somatic mutation (at the C-terminus; 3’ end) is acquired on the other CEBPA allele (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 mutations in the C-terminus region of CEBPA. In some cases, more than one C-terminus mutation can be acquired, suggesting two distinct episodes of AML in one individual.[3] Patients with CEBPA germline pathogenic variants often acquire GATA2 somatic mutations 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 mutation (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 mutations (particularly biallelic CEBPA somatic mutations).

References

1. Leroy H, Roumier C, Huyghe P, et al.: CEBPA point mutations in hematological malignancies. Leukemia 19 (3): 329-34, 2005. [PUBMED Abstract]
2. Kraft IL, Godley LA: Identifying potential germline variants from sequencing hematopoietic malignancies. Blood 136 (22): 2498-2506, 2020. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]

CEBPA-associated familial AML is similar to sporadic AML with somatic biallelic CEBPA mutations 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 CEBPA pathogenic 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. [PUBMED Abstract]
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. [PUBMED Abstract]

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