Acute Myeloid Leukaemia with Germline CEBPA Mutation
Matthew Kilpatrick, MD and Daynna J. Wolff, PhD
Acute Myeloid Leukemia
Cancer Sub-Classification / Subtype
Acute Myeloid Leukemia (AML) with CEBPA germline mutations.
Definition / Description of Disease
This is a distinct entity in the World Health Organization (WHO) classification system within the section of Myeloid Neoplasms with Germline Predisposition.
Patients with germline CEBPA mutations have a rare inherited predisposition for acute myeloid leukemia. CEBPA mutation can occur as an acquired somatic mutation in sporadic AML or as a germline mutation that is inherited across multiple generations of affected family.
Families with germline CEBPA mutation typically inherit an N-terminal frameshift or nonsense mutation in one allele that predisposes to acquiring a somatic C-terminal CEBPA mutation on the other allele with high penetrance. However, there a couple of reports of inheritance of a C-terminal germline variant with reduced penetrance 
Synonyms / Terminology
Epidemiology / Prevalence
- Studies of large series of normal-karyotype AML have reported a frequency of CEBPA mutation of 8% to 13%; among these, 7% to 11% have germline CEBPA mutations. 
- Average age of presentation is 24.5 years (1.75–46 years).
Familial and sporadic CEPBA -mutated cases share morphological and immunophenotypic features in common; therefore, patients with AML with germline CEBPA mutation may be indistinguishable from CEBPA-mutated sporadic AML, both clinically and by mutations. Patients with familial AML with mutated CEBPA have an increased risk for AML relapse; however, the prognosis is favorable which is thought to be due to novel mutations that are not clonally related to the initial disease. Clinical features, age of onset of AML and family history can provide useful clues in identifying patients with germline CEBPA mutations, which are inherited in an autosomal dominant fashion and are highly penetrant.
Sites of Involvement
- AML with CEBPA mutation affects the hematopoietic and lymphatic systems.
Morphologically, AML with mutated CEBPA often presents as AML with minimal differentiation or AML without maturation associated with normal karyotype. The blasts may show frequent Auer rods.
The blasts in AML with germline CEBPA mutations often express aberrant CD7 by flow cytometry. 
Chromosomal Rearrangements (Gene Fusions)
Characteristic Chromosomal Aberrations / Patterns
Often found in chromosomally normal AML.
No typical pattern
Gene Mutations (SNV/INDEL)
The first germline mutation in CEBPA, an N-terminal (212delC) mutation that resulted in a 30-kDa protein with an alternative start site, leading to loss of a transactivation domain. Similar frameshift insertions and deletions at the N-terminus are the most common variants in families with AML with germline CEBPA. In familial cases with germline CEBPA, typically a somatic C-terminal insertions or deletions is the second hit, suggesting that the AML was caused by biallelic CEBPA inactivation. Only a few cases have been reported to have a germline C-terminal mutations in CEBPA.
None at this time
Genes and Main Pathways Involved
The intron-less CEBPA gene encodes a protein that belongs to the basic region leucine zipper family of transcription factors that contains 2 transactivation domains, TAD1 and TAD2; a basic region mediating DNA binding; and a leucine zipper region (Zip) for dimerization. 
Diagnostic Testing Methods
Diagnosis of AML with germline CEPBA mutations is based on detection of the causal genetic abnormality in germline tissue (ie, non-hematologic cells).
Evaluation of CEBPA mutation is required for any new AML with normal karyotype, as the 2016 World Health Organization classification recognizes AML with biallelic CEBPA mutation as a distinct entity of AML with recurrent genetic abnormalities. Clinical testing for the CEBPA gene is available either as a single gene assay or as part of gene panels. Because of the variations in the mutations, sequencing the entire CEBPA gene is recommended. If familial inheritance is suspected, additional testing for germline variant is recommended.
Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)
Acute myeloid leukemia patients with CEBPA mutations have a favorable clinical outcome, but the favorable outcome is limited to those with double mutations (mutations on each allele).
Concurrent FLT3 ITD, NPM1, or GATA2 mutations have also been reported and may indicate the heterogeneity in CEBPA mutated AML.
Individuals with germline CEBPA mutation–associated AML may recur with a different somatic CEBPA mutation, whereas in sporadic AML the CEBPA mutation appears stable throughout the disease course.
Although the recurrence is triggered by independent clones, the patients can still achieve a durable response to therapy and favorable long-term outcome.
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- ↑ 1.0 1.1 Peterson LC, et al., (2017). Myeloid neoplasms with germline predisposition, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p124-125.
- ↑ 2.0 2.1 2.2 2.3 2.4 Gao, Juehua; et al. (2019). "Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists". Archives of Pathology & Laboratory Medicine. 143 (1): 13–22. doi:10.5858/arpa.2017-0194-RA. ISSN 1543-2165. PMID 29372845.
- ↑ 3.0 3.1 Pabst, Thomas; et al. (2008). "Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 26 (31): 5088–5093. doi:10.1200/JCO.2008.16.5563. ISSN 1527-7755. PMID 18768433.
- ↑ 4.0 4.1 Rio-Machin, Ana; et al. (2020). "The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants". Nature Communications. 11 (1): 1044. doi:10.1038/s41467-020-14829-5. ISSN 2041-1723. PMC 7042299 Check
|pmc=value (help). PMID 32098966 Check
- ↑ 5.0 5.1 Pathak, Anand; et al. (2016). "Whole exome sequencing reveals a C-terminal germline variant in CEBPA-associated acute myeloid leukemia: 45-year follow up of a large family". Haematologica. 101 (7): 846–852. doi:10.3324/haematol.2015.130799. ISSN 1592-8721. PMC 5004464. PMID 26721895.
- ↑ 6.0 6.1 6.2 Taskesen, Erdogan; et al. (2011). "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): 2469–2475. doi:10.1182/blood-2010-09-307280. ISSN 1528-0020. PMID 21177436.
- ↑ 7.0 7.1 Pabst, Thomas; et al. (2008). "Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 26 (31): 5088–5093. doi:10.1200/JCO.2008.16.5563. ISSN 1527-7755. PMID 18768433.
- ↑ 8.0 8.1 8.2 Tawana, Kiran; et al. (2015). "Disease evolution and outcomes in familial AML with germline CEBPA mutations". Blood. 126 (10): 1214–1223. doi:10.1182/blood-2015-05-647172. ISSN 1528-0020. PMID 26162409.
- ↑ 9.0 9.1 9.2 Czuchlewski, David R.; et al. (2016-03). "Myeloid Neoplasms with Germline Predisposition". Surgical Pathology Clinics. 9 (1): 165–176. doi:10.1016/j.path.2015.09.010. ISSN 1875-9181. Check date values in:
- ↑ Smith, Matthew L.; et al. (2004). "Mutation of CEBPA in familial acute myeloid leukemia". The New England Journal of Medicine. 351 (23): 2403–2407. doi:10.1056/NEJMoa041331. ISSN 1533-4406. PMID 15575056.
- ↑ Nanri, Tomoko; et al. (2010). "A family harboring a germ-line N-terminal C/EBPalpha mutation and development of acute myeloid leukemia with an additional somatic C-terminal C/EBPalpha mutation". Genes, Chromosomes & Cancer. 49 (3): 237–241. doi:10.1002/gcc.20734. ISSN 1098-2264. PMID 19953636.
- ↑ Renneville, A.; et al. (2009). "Another pedigree with familial acute myeloid leukemia and germline CEBPA mutation". Leukemia. 23 (4): 804–806. doi:10.1038/leu.2008.294. ISSN 1476-5551. PMID 18946494.
- ↑ Sellick, G. S.; et al. (2005). "Further evidence that germline CEBPA mutations cause dominant inheritance of acute myeloid leukaemia". Leukemia. 19 (7): 1276–1278. doi:10.1038/sj.leu.2403788. ISSN 0887-6924. PMID 15902292.
- ↑ "CEBPA". Wikipedia. 2019.
- ↑ Preudhomme, Claude; et al. (2002). "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): 2717–2723. doi:10.1182/blood-2002-03-0990. ISSN 0006-4971. PMID 12351377.
- ↑ Green, Claire L.; et al. (2013). "GATA2 mutations in sporadic and familial acute myeloid leukaemia patients with CEBPA mutations". British Journal of Haematology. 161 (5): 701–705. doi:10.1111/bjh.12317. ISSN 1365-2141. PMID 23560626.
- ↑ Tiesmeier, Jens; et al. (2003). "Evidence for allelic evolution of C/EBPalpha mutations in acute myeloid leukaemia". British Journal of Haematology. 123 (3): 413–419. doi:10.1046/j.1365-2141.2003.04618.x. ISSN 0007-1048. PMID 14616999.
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*Citation of this Page: Kilpatrick M, Wolff DJ. “Acute Myeloid Leukaemia with Germline CEBPA Mutation”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 08/10/2022, https://ccga.io/index.php/Acute_Myeloid_Leukaemia_with_Germline_CEBPA_Mutation.