Leukemic IDH1 and IDH2 Mutations Result in a Hypermethylation Phenotype, Disrupt TET2 Function, and Impair Hematopoietic Differentiation

ME Figueroa, O Abdel-Wahab, C Lu, PS Ward, J Patel, A Shih, YS Li, N Bhagwat, A Vasanthakumar, HF Fernandez, MS Tallman, ZX Sun, K Wolniak, Justine Peeters, W (Wei) Liu, SE Choe, VR Fantin, E Paietta, Bob Löwenberg, JD LichtLA Godley, Ruud Delwel, Peter Valk, CB Thompson, RL Levine, A Melnick

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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 alpha-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.
Original languageUndefined/Unknown
Pages (from-to)553-567
Number of pages15
JournalCancer Cell
Volume18
Issue number6
DOIs
Publication statusPublished - 2010

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