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

Overview

MeSH Major

  • DNA Methylation
  • DNA-Binding Proteins
  • Isocitrate Dehydrogenase
  • Leukemia, Myeloid, Acute
  • Mutation
  • Myeloid Cells
  • Proto-Oncogene Proteins

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.

publication date

  • December 14, 2010

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4105845

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2010.11.015

PubMed ID

  • 21130701

Additional Document Info

start page

  • 553

end page

  • 67

volume

  • 18

number

  • 6