title: Reactive Oxygen Species and Mitochondrial DNA Damage and Repair in BCR-ABL1 Cells Resistant to Imatinib.
abstract: Imatinib revolutionized the therapy of chronic myeloid leukemia (CML), but the resistance to it became an emerging problem. We reported previously that CML cells expressing the BCR/ABL1 fusion gene, accumulated a high level of reactive oxygen species (ROS) due to deregulated mitochondrial electron transport chain, which in turn led to genomic instability, resulting in imatinib resistance. In the present work, we hypothesize that imatinib-resistant cells may show higher instability of mitochondrial DNA (mtDNA) than their sensitive counterparts. To verify this hypothesis, we checked the ROS level and mtDNA damage and repair in model CML cells sensitive and resistant to imatinib and exposed to doxorubicin (DOX), a DNA-damaging agent. The extent of endogenous ROS in imatinib-resistant cells was higher than in their sensitive counterparts and DOX potentiated this relationship. ROS level in cells with primary resistance, which resulted from the T315I mutation in BCR/ABL1, was higher than in cells with acquired resistance. DOX-induced mtDNA damage in T315I imatinib-resistant cells was more pronounced than in imatinib-sensitive cells. All kinds of cells were repairing mtDNA damage with similar kinetics. In conclusion, imatinib-resistant cells can show increased instability of mtDNA, which can result from increased ROS production.
authors: Department of Molecular Genetics, University of Lodz , Lodz, Poland .
authors: Janusz
authors: J
authors: Blasiak
authors: Department of Clinical Cytobiology, Medical Center for Postgraduate Education , Warsaw, Poland .
authors: Grazyna
authors: G
authors: Hoser
authors: Department of Infectious and Liver Diseases, Medical University of Lodz , Lodz, Poland .
authors: Jolanta
authors: J
authors: Bialkowska-Warzecha
authors: Department of Orthodontics, Medical University of Lodz , Lodz, Poland .
authors: Elzbieta
authors: E
authors: Pawlowska
authors: Department of Microbiology and Immunology, School of Medicine, Temple University , Philadelphia, Pennsylvania.
authors: Tomasz
authors: T
authors: Skorski
keywords: BCR-ABL1; DNA repair; imatinib resistance; mitochondrial DNA damage/repair; reactive oxygen species