Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania, PA 19122, USA

Correspondence to: T Skorski, E-mail: tskorski@astro.temple.edu

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.

Oncogene (2002) 21, 8591-8604. doi:10.1038/sj.onc.1206087

DNA damage; DNA repair; apoptosis; checkpoint