title: BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance.
abstract: Mutations in the BCR/ABL kinase domain play a major role in resistance to imatinib mesylate (IM). We report here that BCR/ABL kinase stimulates reactive oxygen species (ROS), which causes oxidative DNA damage, resulting in mutations in the kinase domain. The majority of mutations involved A/T-->G/C and G/C-->A/T transitions, a phenotype detected previously in patients, which encoded clinically relevant amino acid substitutions, causing IM resistance. This effect was reduced in cells expressing BCR/ABL(Y177F) mutant, which does not elevate ROS. Inhibition of ROS in leukemia cells by the antioxidants pyrrolidine dithiocarbamate (PDTC), N-acetylcysteine (NAC), and vitamin E (VE) decreased the mutagenesis rate and frequency of IM resistance. Simultaneous administration of IM and an antioxidant exerted better antimutagenic effect than an antioxidant alone. Therefore, inhibition of ROS should diminish mutagenesis and enhance the effectiveness of IM.
authors.affiliation: Department of Microbiology and Immunology, School of Medicine and the Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19140, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Koptyra
authors.forename: Rafal
authors.initials: R
authors.lastname: Falinski
authors.forename: Michal O
authors.initials: MO
authors.lastname: Nowicki
authors.forename: Tomasz
authors.initials: T
authors.lastname: Stoklosa
authors.forename: Ireneusz
authors.initials: I
authors.lastname: Majsterek
authors.forename: Margaret
authors.initials: M
authors.lastname: Nieborowska-Skorska
authors.forename: Janusz
authors.initials: J
authors.lastname: Blasiak
authors.forename: Tomasz
authors.initials: T
authors.lastname: Skorski
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D051379:Mice; D016513:Mice, SCID; D016296:Mutagenesis; D010084:Oxidation-Reduction; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl