Abstract:
: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.
journal_name
Bloodjournal_title
Bloodauthors
Nowicki MO,Falinski R,Koptyra M,Slupianek A,Stoklosa T,Gloc E,Nieborowska-Skorska M,Blasiak J,Skorski Tdoi
10.1182/blood-2004-05-1941subject
Has Abstractpub_date
2004-12-01 00:00:00pages
3746-53issue
12eissn
0006-4971issn
1528-0020pii
2004-05-1941journal_volume
104pub_type
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