Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis

Abstract

C/EBPα (CEBPA) is mutated in approximately 8 % of AML in both familial and sporadic AML and, with FLT3 and NPM1, has received most attention as a predictive marker of outcome in patients with normal karyotype disease. Mutations clustering to either the N- or C-terminal (N-and C-ter) portions of the protein have different consequences on the protein function. In familial cases the N-ter form is inherited with patients exhibiting long latency period before the onset of overt disease, typically with the acquisition of a C-ter mutation. Despite the essential insights murine models provide the functional consequences of wild-type C/EBPα in human hematopoiesis and how different mutations are involved in AML development have received less attention. Our data underline the critical role of C/EBPα in human hematopoiesis and demonstrate that C/EBPα mutations (alone or in combination) are insufficient to convert normal human hematopoietic stem/progenitors (HSC/HPCs) into leukemic initiating cells, although individually each altered normal hematopoiesis. It provides the first insight into the effects of N- and C-terminal mutations acting alone and to the combined effects of N/C double mutants. Our results mimicked closely what happens in CEBPA mutated patients.