Title

NrasG12D oncoprotein inhibits apoptosis of pre-leukemic cells expressing Cbfbeta-SMMHC via activation of MEK/ERK axis

UMMS Affiliation

Program in Gene Function and Expression

Date

7-17-2014

Document Type

Article

Disciplines

Cancer Biology | Genetics and Genomics

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 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.

Rights and Permissions

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 Jul 17;124(3):426-36. doi: 10.1182/blood-2013-12-541730. Link to article on publisher's site

Comments

First author Liting Xue is a doctoral student in the Cancer Biology program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.

Related Resources

Link to Article in PubMed

Keywords

Acute Myeloid Leukemia, Cbfβ-SMMHC, Nras, Bim, MEK

PubMed ID

24894773