BCR/ABL regulates response to DNA damage: the role in resistance to genotoxic treatment and in genomic instability.
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.
Skorski
Tomasz
T
Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, PA 19122, USA. tskorski@astro.temple.edu
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D004249:DNA Damage; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D009153:Mutagens; D011505:Protein-Tyrosine Kinases / Q000502:physiology*
D000970:Antineoplastic Agents; D009153:Mutagens; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl