BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability

Oncogene. 2002 Dec 9;21(56):8591-604. doi: 10.1038/sj.onc.1206087.


BCR/ABL regulates cell proliferation, apoptosis, differentiation and adhesion. In addition, BCR/ABL can induce resistance to cytostatic drugs and irradiation by modulation of DNA repair mechanisms, cell cycle checkpoints and Bcl-2 protein family members. Upon DNA damage BCR/ABL not only enhances reparation of DNA lesions (e.g. homologous recombination repair), but also prolongs activation of cell cycle checkpoints (e.g. G2/M) providing more time for repair of otherwise lethal lesions. Moreover, by modification of anti-apoptotic members of the Bcl-2 family (e.g. upregulation of Bcl-x(L)) BCR/ABL provides a cytoplasmic 'umbrella' protecting mitochondria from the 'rain' of apoptotic signals coming from the damaged DNA in the nucleus, thus preventing release of cytochrome c and activation of caspases. The unrepaired and/or aberrantly repaired (but not lethal) DNA lesions resulting from spontaneous and/or drug-induced damage can accumulate in BCR/ABL-transformed cells leading to genomic instability and malignant progression of the disease. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, imatinib mesylate) reverses drug resistance and, in combination with standard chemotherapeutics can exert strong anti-leukemia effect.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis
  • DNA Damage*
  • Fusion Proteins, bcr-abl
  • Humans
  • Mutagens*
  • Protein-Tyrosine Kinases / physiology*


  • Antineoplastic Agents
  • Mutagens
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl