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

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.

• Authors: Lev M Kats, Markus Reschke, Riccardo Taulli, Olga Pozdnyakova, Kerri Burgess, Parul Bhargava, Kimberly Straley, Rahul Karnik, Alexander Meissner, Donald Small, Shinsan M Su, Katharine Yen, Jiangwen Zhang, Pier Paolo Pandolfi
• Journal: Cell stem cell (Cell Stem Cell) Vol. 14 Issue 3 Pg. 329-41 (Mar 06 2014) ISSN: 1875-9777 [Electronic] United States
• PMID: 24440599 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Homeodomain Proteins
• Myeloid Ecotropic Viral Integration Site 1 Protein
• Neoplasm Proteins
• homeobox protein HOXA9
• Isocitrate Dehydrogenase
• Flt3 protein, mouse
• fms-Like Tyrosine Kinase 3

Topics

• Animals
• Bone Marrow (pathology)
• Carcinogenesis (genetics, pathology)
• Cell Differentiation
• Cell Proliferation
• Cell Transformation, Neoplastic (pathology)
• Disease Models, Animal
• Erythroid Cells (metabolism, pathology)
• Hematopoiesis
• Hematopoietic Stem Cells (pathology)
• Homeodomain Proteins (metabolism)
• Isocitrate Dehydrogenase (genetics, metabolism)
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation (genetics)
• Myeloid Ecotropic Viral Integration Site 1 Protein
• Neoplasm Proteins (metabolism)
• Oncogenes
• Spleen (pathology)
• Transcription, Genetic
• fms-Like Tyrosine Kinase 3 (metabolism)