RAS oncogene suppression induces apoptosis followed by more differentiated and less myelosuppressive disease upon relapse of acute myeloid leukemia

Won Il Kim, Ilze Matise, Miechaleen D. Diers, David A Largaespada

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

To study the oncogenic role of the NRAS oncogene (NRAS G12V) in the context of acute myeloid leukemia (AML), we used a Vav promoter-tetracycline transactivator (Vav-tTA)-driven repressible TRENRAS G12V transgene system in Mll-AF9 knock-in mice developing AML. Conditional repression of NRAS G12V expression greatly reduced peripheral white blood cell (WBC) counts in leukemia recipient mice and induced apoptosis in the transplanted AML cells correlated with reduced Ras/Erk signaling. After marked decrease of AML blast cells, myeloproliferative disease (MPD)-like AML relapsed characterized by cells that did not express NRAS G12V. In comparison with primary AML, the MPD-like AML showed significantly reduced aggressiveness, reduced myelosuppression, and a more differentiated phenotype. We conclude that, in AML induced by an Mll-AF9 transgene, NRAS G12V expression contributes to acute leukemia maintenance by suppressing apoptosis and reducing differentiation of leukemia cells. Moreover, NRAS G12V oncogene has a cell nonautonomous role in suppressing erythropoiesis that results in the MPD-like AML show significantly reduced ability to induce anemia. Our results imply that targeting NRAS or RAS oncogene-activated pathways is a good therapeutic strategy forAMLand attenuating aggressiveness of relapsed AML.

Original languageEnglish (US)
Pages (from-to)1086-1096
Number of pages11
JournalBlood
Volume113
Issue number5
DOIs
StatePublished - Jan 29 2009

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