Genetic profiling of familial CEBPA-mutated AML. (A) Distribution of germline and acquired CEBPA mutations in familial AML. Transactivation domain (TAD) 1 amino acids (AA) 70 to 97; p30 start codon (ATG), AA 120; TAD2, AA 126 to 200; DNA-binding domain (DBD), AA 278 to 306; leucine zipper domain (LZD), AA 307 to 358. All germline mutations were localized to the N-terminal, causing a frameshift preceding the internal CEBPA-p30 start codon. Somatic mutations (detailed in supplemental Table 2) clustered in the C-terminal of the gene, with a hotspot located at p.K313. (B) Comparison of mutation profiles between familial and sporadic CEBPA-mutant AML. Mutation profiles are shown for familial and sporadic CEBPA-mutated AML samples (the latter analyzed within TCGA consortium33 ). All coding genes harboring ≥2 mutations across the 200 sporadic AML exomes and ≥1 mutation in familial or sporadic CEBPA-mutated AML are shown. In general, sporadic CEBPAsm tumors (predominantly with a lone C-terminal mutation) harbored more mutations than primary familial or sporadic CEBPAdm AML. GATA2 and WT1 mutations were most frequently observed in familial AML and were mutually exclusive. In familial AML, WT1 mutations localized to the transcription regulatory N-terminal, contrasting with sporadic CEBPA-mutated samples and previous reports of NK-AML, where WT1 mutations target the C-terminal exons 7 and 9.43 Identical CSF3R (p.T618I) mutations were detected in both familial and sporadic CEBPA-mutated AML, as previously reported in chronic neutrophilic leukemia.44,45 Regions of chromosomal loss and aUPD were identified using WES data in familial AML, and with high-resolution SNP array in TCGA cohort.
