NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis

Abstract

Acute myeloid leukemia (AML) results from the activity of driver mutations that deregulate proliferation and survival of hematopoietic stem cells (HSCs). The fusion protein CBFβ-SMMHC impairs differentiation in hematopoietic stem and progenitor cells and induces AML in cooperation with other mutations. However, the combined function of CBFβ-SMMHC and cooperating mutations in preleukemic expansion is not known. Here, we used NrasLSL-G12D; Cbfb56M knock-in mice to show that allelic expression of oncogenic NrasG12D and Cbfβ-SMMHC increases survival of preleukemic short-term HSCs and myeloid progenitor cells and maintains the differentiation block induced by the fusion protein. NrasG12D and Cbfβ-SMMHC synergize to induce leukemia in mice in a cell-autonomous manner, with a shorter median latency and higher leukemia-initiating cell activity than that of mice expressing Cbfβ-SMMHC. Furthermore, NrasLSL-G12D; Cbfb 56M leukemic cells were sensitive to pharmacologic inhibition of the MEK/ERK signaling pathway, increasing apoptosis and Bim protein levels. These studies demonstrate that Cbfβ-SMMHC and NrasG12D promote the survival of preleukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inversion(16) AML-targeted therapies. © 2014 by The American Society of Hematology.