Proto-Oncogenic Role of Mutant IDH2 in Leukemia Initiation and Maintenance

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• 作者：Lev M. Kats¹ ; ⁹ ; Markus Reschke¹ ; ⁹ ; Riccardo Taulli¹ ; Olga Pozdnyakova² ; Kerri Burgess¹ ; Parul Bhargava¹ ; Kimberly Straley³ ; Rahul Karnik⁴ ; ⁵ ; ⁶ ; Alexander Meissner⁴ ; ⁵ ; ⁶ ; Donald Small⁷ ; Shinsan M. Su³ ; Katharine Yen³ ; Jiangwen Zhang⁸ ; Pier Paolo Pandolfi¹ ; ^{ppandolf@bidmc.harvard.edu" class="auth_mail}
• 刊名：Cell Stem Cell
• 出版年：6 March, 2014
• 年：2014
• 卷：14
• 期：3
• 页码：329-341
• 全文大小：2917 K

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Summary

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聽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聽vivo. Critically, we show that genetic deinduction of mutant IDH2 in leukemic cells in聽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.