4.7 Article

NRAS9G12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

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BLOOD
卷 124, 期 22, 页码 3274-3283

出版社

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-08-521708

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资金

  1. National Institutes of Health [NIH] National Cancer Institute [P30 CA77598]
  2. NIH National Heart, Lung, and Blood Institute [T32HL007062]
  3. Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota
  4. Leukemia and Lymphoma Society Specialized Center of Research
  5. NIH National Cancer Institute [R37CA72614]
  6. Leukemia and Lymphoma Society Specialized Center of Research Award LLS [7019-04]
  7. Department of Defense (CDMRP) Ovarian Cancer Teal Innovator Award
  8. National Heart, Lung and Blood Institute, NIH [N01-HV-00242]
  9. National Cancer Institute, NIH [1R01CA130826]

向作者/读者索取更多资源

Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors MII-AF9 and a tetracycline-repressible, activated NRAS (NRAS(G12v)). Using computational approaches to explore our gene-expression data sets, we found that NRAS(G12V) enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9 and Myb-dependent leukemia self-renewal geneexpression program. NRAS(G12v) was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRAS(G12v)-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1I-0 w cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12v) withdrawal. NRAS(G12v) 'maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell specific therapies. Together, these experimental results define a RAS oncogene driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.

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