Mutant IDH1 Downregulates ATM and Alters DNA Repair and Sensitivity to DNA Damage Independent of TET2 Academic Article uri icon

Overview

MeSH Major

  • Ataxia Telangiectasia Mutated Proteins
  • DNA Damage
  • DNA Repair
  • DNA-Binding Proteins
  • Hematopoietic Stem Cells
  • Isocitrate Dehydrogenase
  • Proto-Oncogene Proteins

abstract

  • Mutations in the isocitrate dehydrogenase-1 gene (IDH1) are common drivers of acute myeloid leukemia (AML) but their mechanism is not fully understood. It is thought that IDH1 mutants act by inhibiting TET2 to alter DNA methylation, but there are significant unexplained clinical differences between IDH1- and TET2-mutant diseases. We have discovered that mice expressing endogenous mutant IDH1 have reduced numbers of hematopoietic stem cells (HSCs), in contrast to Tet2 knockout (TET2-KO) mice. Mutant IDH1 downregulates the DNA damage (DD) sensor ATM by altering histone methylation, leading to impaired DNA repair, increased sensitivity to DD, and reduced HSC self-renewal, independent of TET2. ATM expression is also decreased in human IDH1-mutated AML. These findings may have implications for treatment of IDH-mutant leukemia.

authors

publication date

  • August 8, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5022794

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2016.05.018

PubMed ID

  • 27424808

Additional Document Info

start page

  • 337

end page

  • 48

volume

  • 30

number

  • 2