Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells

Oncogene. 2008 Jul 17;27(31):4380-4. doi: 10.1038/onc.2008.68. Epub 2008 Mar 24.


Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Benzamides
  • Chromosome Aberrations
  • DNA Damage
  • DNA Repair*
  • Dasatinib
  • Fibroblasts / metabolism
  • Fusion Proteins, bcr-abl / biosynthesis*
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Imatinib Mesylate
  • Kinetics
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / radiation effects
  • Mice
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-abl / antagonists & inhibitors
  • Proto-Oncogene Proteins c-abl / physiology*
  • Pyrimidines / pharmacology
  • Thiazoles / pharmacology


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Thiazoles
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Proto-Oncogene Proteins c-abl
  • Dasatinib