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Cancer Res. 2015 May 15;75(10):2005-16. doi: 10.1158/0008-5472.CAN-14-2200. Epub 2015 Mar 20.

IDH2 and NPM1 Mutations Cooperate to Activate Hoxa9/Meis1 and Hypoxia Pathways in Acute Myeloid Leukemia.

Author information

1
Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
2
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata, Japan.
3
R&D Division, Daiichi Sankyo Co., Ltd., Tokyo, Japan.
4
Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan. ikitabay@ncc.go.jp.

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.

PMID:
25795706
DOI:
10.1158/0008-5472.CAN-14-2200
[Indexed for MEDLINE]
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