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Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

GSE24505 Homo sapiens Expression profiling by array; Methylation profiling by genome tiling array 757 samples Submitted 2010/12/03 Platform GPL6602Platform GPL6604
Summary
Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large 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 rapidly 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 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 cell marker expression, suggesting a shared pro-leukemogenic effect.
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Also filed as BioProject PRJNA132611. Searching any of these in the dataset finder brings you back here.

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