| Literature DB >> 24440599 |
Lev M Kats1, Markus Reschke1, Riccardo Taulli1, Olga Pozdnyakova2, Kerri Burgess1, Parul Bhargava1, Kimberly Straley3, Rahul Karnik4, Alexander Meissner4, Donald Small5, Shinsan M Su3, Katharine Yen3, Jiangwen Zhang6, Pier Paolo Pandolfi7.
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.Entities:
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Year: 2014 PMID： 24440599 PMCID： PMC4380188 DOI： 10.1016/j.stem.2013.12.016
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633