Journal
BLOOD
Volume 104, Issue 12, Pages 3746-3753Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2004-05-1941
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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. (C) 2004 by The American Society of Hematology.
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