| First Author | Xue L | Year | 2014 |
| Journal | Blood | Volume | 124 |
| Issue | 3 | Pages | 426-36 |
| PubMed ID | 24894773 | Mgi Jnum | J:214458 |
| Mgi Id | MGI:5603006 | Doi | 10.1182/blood-2013-12-541730 |
| Citation | Xue L, et al. (2014) NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing Cbfbeta-SMMHC via activation of MEK/ERK axis. Blood 124(3):426-36 |
| abstractText | 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 preleukemic expansion is not known. Here, we used Nras(LSL-G12D); Cbfb(56M) knock-in mice to show that allelic expression of oncogenic Nras(G12D) and Cbfbeta-SMMHC increases survival of preleukemic short-term HSCs and myeloid progenitor cells and maintains the differentiation block induced by the fusion protein. Nras(G12D) and Cbfbeta-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 Cbfbeta-SMMHC. Furthermore, Nras(LSL-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 Cbfbeta-SMMHC and Nras(G12D) promote the survival of preleukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define Nras(LSL-G12D); Cbfb(56M) mice as a valuable genetic model for the study of inversion(16) AML-targeted therapies. |
