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Medline ® Abstract for Reference 192

of '慢性髓系白血病的细胞和分子生物学'

BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks.
Nowicki MO, Falinski R, Koptyra M, Slupianek A, Stoklosa T, Gloc E, Nieborowska-Skorska M, Blasiak J, Skorski T
Blood. 2004;104(12):3746. Epub 2004 Aug 10.
The oncogenic BCR/ABL tyrosine kinase induces constitutive DNA damage in Philadelphia chromosome (Ph)-positive leukemia cells. We find that BCR/ABL-induced reactive oxygen species (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S and G(2)/M cell cycle phases. These lesions are repaired by BCR/ABL-stimulated homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) mechanisms. A high mutation rate is detected in HRR products in BCR/ABL-positive cells, but not in the normal counterparts. In addition, large deletions are found in NHEJ products exclusively in BCR/ABL cells. We propose that the following series of events may contribute to genomic instability of Ph-positive leukemias: BCR/ABL -->ROSs -->oxidative DNA damage -->DSBs in proliferating cells -->unfaithful HRR and NHEJ repair.
Center for Biotechnology, College of Science and Technology, Temple University, Bio-Life Sciences Bldg, Rm 419, 1900 N 12th St, Philadelphia, PA 19122, USA.