Identification of novel CEBPA double mutations capable of promoting familial AML via the suppression of myeloid differentiation.

CCAAT-enhancer-binding protein α (CEBPA) gene carrying two mutations (CEBPA double mutations) is known to promote familial acute myeloid leukemia (AML). However, the underlying mechanism by which CEBPA double mutations promote AML remains poorly understood. Here we report that a family with three generations suffering from familial AML carries novel double mutations of CEBPA. Seven bases of GCGCGGG were inserted into the N-terminal c.113-114 of CEBPA as germline mutations and three bases of AAG were inserted into the C-terminal c.939-940 as a somatic mutation. To test the functional impact of this double mutation, we constructed plasmid encoding the double mutants of CEBPA and transfected it into the myeloid precursor 32Dcl3 cells. Lentiviral induced overexpression of CEBPA with these double mutations inhibited myeloid differentiation of these 32Dcl3 cells, and led to approximately 4-fold fewer frequency of CD11b expression. Our results confirm that the double mutations of CEBPA at both N- and C-terminals are potentially to induce leukemogenesis of AML.