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

Research output: Contribution to journalArticle

21 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

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Acute Myeloid Leukemia
Isocitrate Dehydrogenase
Mutation
Hematopoietic Stem Cells
Enzymes
Stem Cells
Maintenance
Dioxygenases
Myeloid Cells
Genes
Hypoxia
Neoplasms
Cell Survival
Leukemia
Gene Expression
Survival
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Ogawara, Y., Katsumoto, T., Aikawa, Y., Shima, Y., Kagiyama, Y., Soga, T., ... 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

IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and Hypoxia pathways in acute myeloid Leukemia. / Ogawara, Yoko; Katsumoto, Takuo; Aikawa, Yukiko; Shima, Yutaka; Kagiyama, Yuki; Soga, Tomoyoshi; Matsunaga, Hironori; Seki, Takahiko; Araki, Kazushi; Kitabayashi, Issay.

In: Cancer Research, Vol. 75, No. 10, 15.05.2015, p. 2005-2016.

Research output: Contribution to journalArticle

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, vol. 75, no. 10, pp. 2005-2016. https://doi.org/10.1158/0008-5472.CAN-14-2200
Ogawara, Yoko ; Katsumoto, Takuo ; Aikawa, Yukiko ; Shima, Yutaka ; Kagiyama, Yuki ; Soga, Tomoyoshi ; Matsunaga, Hironori ; Seki, Takahiko ; Araki, Kazushi ; Kitabayashi, Issay. / IDH2 and NPM1 mutations cooperate to activate Hoxa9/Meis1 and Hypoxia pathways in acute myeloid Leukemia. In: Cancer Research. 2015 ; Vol. 75, No. 10. pp. 2005-2016.
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AU - Shima, Yutaka

AU - Kagiyama, Yuki

AU - Soga, Tomoyoshi

AU - Matsunaga, Hironori

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