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

Overview

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.

authors

  • Figueroa, Maria E
  • Abdel-wahab, Omar
  • Lu, Chao
  • Ward, Patrick S
  • Patel, Jay
  • Shih, Alan
  • Li, Yushan
  • Bhagwat, Neha
  • Vasanthakumar, Aparna
  • Fernandez, Hugo F
  • Tallman, Martin S
  • Sun, Zhuoxin
  • Wolniak, Kristy
  • Peeters, Justine K
  • Liu, Wei
  • Choe, Sung E
  • Fantin, Valeria R
  • Paietta, Elisabeth
  • Löwenberg, Bob
  • Licht, Jonathan D
  • Godley, Lucy A
  • Delwel, Ruud
  • Valk, Peter J M
  • Thompson, Craig B
  • Levine, Ross L.
  • Melnick, Ari M.

publication date

  • December 9, 2010

Research

keywords

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

Identity

PubMed Central ID

  • PMC4105845

Scopus Document Identifier

  • 78650019179

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2010.11.015

PubMed ID

  • 21130701

Additional Document Info

volume

  • 18

issue

  • 6