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Cell Stem Cell DOI:10.1016/j.stem.2013.12.016

Proto-oncogenic role of mutant IDH2 in leukemia initiation and maintenance.

Publication TypeJournal Article
Year of Publication2014
AuthorsKats, LM, Reschke, M, Taulli, R, Pozdnyakova, O, Burgess, K, Bhargava, P, Straley, K, Karnik, R, Meissner, A, Small, D, Su, SM, Yen, K, Zhang, J, Pandolfi, PPaolo
JournalCell Stem Cell
Volume14
Issue3
Pages329-41
Date Published2014 Mar 06
ISSN1875-9777
KeywordsAnimals, Bone Marrow, Carcinogenesis, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Disease Models, Animal, Erythroid Cells, fms-Like Tyrosine Kinase 3, Hematopoiesis, Hematopoietic Stem Cells, Homeodomain Proteins, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Neoplasm Proteins, Oncogenes, Spleen, Transcription, Genetic
Abstract

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.

URLhttp://linkinghub.elsevier.com/retrieve/pii/S1934-5909(13)00595-X
DOI10.1016/j.stem.2013.12.016
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24440599?dopt=Abstract

Alternate JournalCell Stem Cell
PubMed ID24440599
PubMed Central IDPMC4380188
Grant ListP30 CA006973 / CA / NCI NIH HHS / United States
R01 CA090668 / CA / NCI NIH HHS / United States