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.
Pubmed ID: 21130701 RIS Download
Mesh terms: 5-Methylcytosine | Cell Differentiation | DNA Methylation | DNA-Binding Proteins | GATA1 Transcription Factor | Gene Regulatory Networks | Humans | Hydroxylation | Isocitrate Dehydrogenase | Leukemia, Myeloid, Acute | Mutation | Myeloid Cells | Phenotype | Proto-Oncogene Proteins | Proto-Oncogenes | Transcription Factors
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