title: IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia.
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.
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yoko
authors: Y
authors: Ogawara
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors: Takuo
authors: T
authors: Katsumoto
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yukiko
authors: Y
authors: Aikawa
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yutaka
authors: Y
authors: Shima
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors: Yuki
authors: Y
authors: Kagiyama
authors: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
authors: Tomoyoshi
authors: T
authors: Soga
authors: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors: Hironori
authors: H
authors: Matsunaga
authors: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors: Takahiko
authors: T
authors: Seki
authors: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors: Kazushi
authors: K
authors: Araki
authors: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan. ikitabay@ncc.go.jp.
authors: Issay
authors: I
authors: Kitabayashi
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D015973:Gene Expression Regulation, Leukemic; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D000090243:Nucleophosmin; D015854:Up-Regulation
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C000716967:NPM1 protein, human; D009363:Neoplasm Proteins; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; C097899:homeobox protein HOXA9; D000090243:Nucleophosmin; D007521:Isocitrate Dehydrogenase; C000599591:isocitrate dehydrogenase 2, mouse