Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance.
Mutations in the metabolic enzymes isocitrate dehydrogenase-1 (IDH1) and IDH2 that produce the oncometabolite D-2-hydroxyglutarate (2-HG) occur frequently in human acute myeloid leukemia (AML). 2-HG modulates numerous biological pathways implicated in malignant transformation, but the contribution of mutant IDH proteins to maintenance and progression of AML in vivo is currently unknown. To answer this crucial question we have generated transgenic mice that express IDH2(R140Q) in an on/off- and tissue-specific manner using a tetracycline-inducible system. We found that IDH2(R140Q) can cooperate with overexpression of HoxA9 and Meis1a and with mutations in FMS-like tyrosine kinase 3 (FLT3) to drive acute leukemia in vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in vivo has profound effects on their growth and/or maintenance. Our data demonstrate the proto-oncogenic role of mutant IDH2 and support its relevance as a therapeutic target for the treatment of human AML.
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Lev M
LM
Kats
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Markus
M
Reschke
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Riccardo
R
Taulli
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA.
Olga
O
Pozdnyakova
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Kerri
K
Burgess
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Parul
P
Bhargava
Agios Pharmaceuticals, Cambridge, MA 02139, USA.
Kimberly
K
Straley
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Rahul
R
Karnik
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
Alexander
A
Meissner
Oncology and Pediatrics, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Donald
D
Small
Agios Pharmaceuticals, Cambridge, MA 02139, USA.
Shinsan M
SM
Su
Agios Pharmaceuticals, Cambridge, MA 02139, USA.
Katharine
K
Yen
School of Biological Sciences, The University of Hong Kong, Hong Kong SAR.
Jiangwen
J
Zhang
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address: ppandolf@bidmc.harvard.edu.
Pier Paolo
PP
Pandolfi
D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D004195:Disease Models, Animal; D041905:Erythroid Cells / Q000378:metabolism / Q000473:pathology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D009857:Oncogenes; D013154:Spleen / Q000473:pathology; D014158:Transcription, Genetic; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
D018398:Homeodomain Proteins; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C097899:homeobox protein HOXA9; D007521:Isocitrate Dehydrogenase; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3