IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and Hypoxia pathways in acute myeloid Leukemia

Yoko Ogawara, Takuo Katsumoto, Yukiko Aikawa, Yutaka Shima, Yuki Kagiyama, Tomoyoshi Soga, Hironori Matsunaga, Takahiko Seki, Kazushi Araki, Issay Kitabayashi

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25 Citations (Scopus)

Abstract

IDH1 and IDH2 mutations occur frequently in acute myeloid leukemia (AML) and other cancers. The mutant isocitrate dehydrogenase (IDH) enzymes convert α-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases. To determine whether mutant IDH enzymes are valid targets for cancer therapy, we created a mouse model of AML in which mice were transplanted with nucleophosmin1 (NPM)+/- hematopoietic stem/progenitor cells cotransduced with four mutant genes (NPMc, IDH2/R140Q, DNMT3A/R882H, and FLT3/ITD), which often occur simultaneously in human AML patients. Conditional deletion of IDH2/R140Q blocked 2-HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. IDH2/R140Q was necessary for the engraftment or survival of NPMc+ cells in vivo. Gene expression analysis indicated that NPMc increased expression of Hoxa9. IDH2/R140Q also increased the level of Meis1 and activated the hypoxia pathway in AML cells. IDH2/R140Q decreased the 5hmC modification and expression of some differentiation-inducing genes (Ebf1 and Spib). Taken together, our results indicated that IDH2 mutation is critical for the development and maintenance of AML stem-like cells, and they provided a preclinical justification for targeting mutant IDH enzymes as a strategy for anticancer therapy.

Original languageEnglish
Pages (from-to)2005-2016
Number of pages12
JournalCancer Research
Volume75
Issue number10
DOIs
Publication statusPublished - 2015 May 15

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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    Ogawara, Y., Katsumoto, T., Aikawa, Y., Shima, Y., Kagiyama, Y., Soga, T., Matsunaga, H., Seki, T., Araki, K., & Kitabayashi, I. (2015). IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and Hypoxia pathways in acute myeloid Leukemia. Cancer Research, 75(10), 2005-2016. https://doi.org/10.1158/0008-5472.CAN-14-2200