Genomic instability: The cause and effect of BCR/ABL tyrosine kinase.
Genes encoding c-ABL kinase and BCR protein are targeted by yet-unknown mechanisms causing DNA double-strand breaks resulting in the generation of a chimeric gene encoding BCR/ABL fusion tyrosine kinase. BCR/ABL kinase displays transforming activity because of its constitutive kinase activity causing deregulated proliferation, apoptosis, differentiation, and adhesion. Moreover, BCR/ABL kinase is able to facilitate DNA repair, prolong activation of G2/M and S cell cycle checkpoints, and elevate expression of the antiapoptotic protein Bcl-X(L), making malignant cells less responsive to antitumor treatment. BCR/ABL may also stimulate generation of reactive oxygen species and enhance spontaneous DNA damage in tumor cells. Unfortunately, BCR/ABL kinase compromises the fidelity of DNA repair mechanisms, thus contributing to the accumulation of additional genetic abnormalities that lead to resistance to inhibitors such as imatinib mesylate and to malignant progression of the disease. Therefore, chronic myelogenous leukemia cells display mutator phenotype.
Skorski
Tomasz
T
Department of Microbiology and Immunology, School of Medicine, Temple University, MRB 548A, 3400 N. Broad Street, Philadelphia, PA 19140, USA. tskorski@temple.edu
D017209:Apoptosis / Q000235:genetics; D001549:Benzamides; D002454:Cell Differentiation / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000502:physiology*; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl