NrasG12D oncoprotein inhibits apoptosis of pre-leukemic cells expressing Cbfbeta-SMMHC via activation of MEK/ERK axis
Program in Gene Function and Expression
Cancer Biology | Genetics and Genomics
Acute myeloid leukemia (AML) results from the activity of driver mutations that deregulate proliferation and survival of hematopoietic stem cells (HSCs). The fusion protein CBFbeta-SMMHC impairs differentiation in hematopoietic stem and progenitor cells, and induces AML in cooperation with other mutations. However, the combined function of CBFbeta-SMMHC and cooperating mutations in pre-leukemic expansion is not known. Here, we used NrasLSL-G12D; Cbfb56M knock-in mice to show that allelic expression of oncogenic NrasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic short-term HSCs and myeloid progenitor cells and maintains the differentiation block induced by the fusion protein. NrasG12D and Cbfbeta-SMMHC synergize to induce leukemia in mice in a cell autonomous manner with a median latency shorter and with higher leukemia-initiating cell activity than that of mice expressing Cbfbeta-SMMHC. Furthermore, NrasLSL-G12D; Cbfb56M leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway, increasing apoptosis and Bim protein levels. These studies demonstrate that Cbfbeta-SMMHC and NrasG12D promote the survival of pre-leukemic 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 inv16 AML targeted therapies.
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Citation:Xue L, Pulikkan JA, Valk PJ, Castilla LH. NrasG12D oncoprotein inhibits apoptosis of pre-leukemic cells expressing Cbfβ-SMMHC via activation of MEK/ERK axis. Blood. 2014 Jun 3. doi:10.1182/blood-2013-12-541730. Link to article on publisher's site
Acute Myeloid Leukemia, Cbfβ-SMMHC, Nras, Bim, MEK