Background: Mutations in the myeloid transcription factor CEBPA (CCAAT enhancer binding protein-alpha) have been implicated in 10–15% of cytogenetically normal (CN) acute myeloid leukemia (AML) patients (pts). At the molecular level, two types of heterozygous CEPBA mutations have been identified. First, nonsense mutations affecting the N-terminal region, preventing the expression of the full-length protein, and second, in-frame mutations located in the basic-region-leucine zipper domain, resulting in a decreased CEBPA DNA-binding or dimerization activity. Clinically, CN-AML with mutant CEBPA is associated with a favorable prognosis. Recently, two independent families were reported in whom several family members affected by AML carried heterozygous germline CEBPA mutations. All germline mutations were located in the N-terminus. In addition, somatically acquired C-terminal mutations were detected in one out of three and two out of four family members, respectively. These findings led to the hypothesis that CEBPA germline mutations predispose to AML and that additional somatically acquired mutations may contribute to the development of the disease.

Aim: To screen CN-AML pts with somatically acquired CEBPA mutations for germline CEBPA mutations as predisposing events for the development of AML.

Methods: Pts were entered in the AML HD98-A or AMLSG 07-04 multicenter treatment trials of the German-Austrian AML Study Group. Buccal mucosa was obtained using commercial FTA filter cards after informed consent; CEBPA mutation screening was performed as recently described.

Results: Buccal DNA from 18 pts exhibiting CEBPA mutations in their leukemic cells (biallelic N-terminal and C-terminal, n=12; heterozygous C-terminal, n=5; heterozygous N-terminal, n=1) was available for analysis. In 16 pts, no CEBPA germline mutations could be detected. In one pt, the heterozygous C-terminal in-frame mutation (1609G>A) that was identified in the diagnostic sample was also present in the germline DNA. In a second pt with an N-terminal deletion and a C-terminal insertion mutation in the diagnostic sample, the N-terminal mutation was also identified in the germline material. Interestingly, the daughter of this pt also developed AML at the age of three years, exhibiting the identical N-terminal germline mutation, while the t C-terminal mutation was acquired and different to that of her mother. None of the remaining family members who could be analyzed had CEBPA germline mutations or a history of leukemia.

Conclusion: The detection of CEBPA germline mutations in another pedigree with familial AML further sustains the hypothesis that CEBPA germline mutations might be the predisposing event in the development of AML in these families. Since other AML-associated gene mutations are rarely detected in CEBPA mutated cases, somatic mutations in the second allele represent a possible ‘second hit’ in this molecularly defined AML subtype.

Author notes

Disclosure: No relevant conflicts of interest to declare.