| Literature DB >> 21130701 |
Maria E Figueroa1, Omar Abdel-Wahab, Chao Lu, Patrick S Ward, Jay Patel, Alan Shih, Yushan Li, Neha Bhagwat, Aparna Vasanthakumar, Hugo F Fernandez, Martin S Tallman, Zhuoxin Sun, Kristy Wolniak, Justine K Peeters, Wei Liu, Sung E Choe, Valeria R Fantin, Elisabeth Paietta, Bob Löwenberg, Jonathan D Licht, Lucy A Godley, Ruud Delwel, Peter J M Valk, Craig B Thompson, Ross L Levine, Ari Melnick.
Abstract
Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2-hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large acute myeloid leukemia (AML) patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of-function mutations were associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem/progenitor cell marker expression, suggesting a shared proleukemogenic effect.Entities:
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Year: 2010 PMID： 21130701 PMCID： PMC4105845 DOI： 10.1016/j.ccr.2010.11.015
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585