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

Cancer cell | Dec 14, 2010

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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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA173636
  • Agency: NCI NIH HHS, Id: U54 CA143798
  • Agency: NCI NIH HHS, Id: CA 114737
  • Agency: NCI NIH HHS, Id: U10 CA021115
  • Agency: Howard Hughes Medical Institute, Id: R01 HL082950
  • Agency: NHLBI NIH HHS, Id: R01 CA105463
  • Agency: NCI NIH HHS, Id: CA21115
  • Agency: NCI NIH HHS, Id: U24 CA114737
  • Agency: NCI NIH HHS, Id: U54CA143798-01
  • Agency: NCI NIH HHS, Id:

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