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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib
Janusz Blasiak1, Grazyna Hoser2, Jolanta Bialkowska-Warzecha3
1Department of Molecular Genetics, University of Lodz, Łódź, Poland.
Abstract:
Imatinib revolutionized the treatment of chronic myeloid leukemia (CML) with the expression of the BCR-ABL1 tyrosine kinase, but imatinib resistance is an emerging problem. Imatinib can hinder the inhibitory effects of BCR-ABL1 on mitochondrial apoptotic pathway, so mitochondrial mutagenesis can be important for its action. To explore the mechanisms of imatinib resistance we created a mouse-derived CML model cells consisting of parental 32D cells (P) and cells transfected with the BCR-ABL1 gene (S cells) or its variants with the Y253H or T315I mutations (253 and 315 cells, respectively), conferring resistance to imatinib. A fraction of the S cells was cultured in increasing concentrations of imatinib, acquiring resistance to this drug (AR cells). The 253, 315 and AR cells, in contrast to S cells, displayed resistance to imatinib. We observed that the T315I cells displayed greater extent of H2O2-induced mtDNA damage than their imatinib-sensitive counterparts. No difference in the sensitivity to UV radiation was observed among all the cell lines. A decrease in the extent of H2O2-induced mtDNA damage was observed during a 120-min repair incubation in all cell lines, but it was significant only in imatinib-sensitive and T315I cells. No difference in the copy number of mtDNA and frequency of the 3,867-bp deletion was observed and genotoxic stress induced by H2O2 or UV did not change this relationship. In conclusion, some aspects of mtDNA mutagenesis, including sensitivity to oxidative stress and DNA repair can contribute to imatinib resistance in BCR-ABL1-expressing cells.
Insights
Mitochondrial DNA (mtDNA) mutations and repair capacity influence imatinib resistance in chronic myeloid leukemia (CML) cells. Understanding these mechanisms may lead to improved CML treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Imatinib is a groundbreaking treatment for chronic myeloid leukemia (CML) targeting the BCR-ABL1 tyrosine kinase.
- Emerging imatinib resistance in CML necessitates exploration of alternative resistance mechanisms.
- Mitochondrial mutagenesis may play a role in imatinib's action by affecting the mitochondrial apoptotic pathway.
Purpose of the Study:
- To investigate the role of mitochondrial DNA (mtDNA) mutagenesis in imatinib resistance in BCR-ABL1-expressing CML cells.
- To compare the sensitivity to oxidative stress and DNA repair capacity of imatinib-resistant and sensitive CML cell lines.
Main Methods:
- Developed a mouse-derived CML model using parental 32D cells and BCR-ABL1 transfected cells (S cells).
- Created imatinib-resistant cell lines through mutations (Y253H, T315I) or adaptation (AR cells).
- Assessed mtDNA damage induced by hydrogen peroxide (H2O2) and UV radiation, and evaluated mtDNA repair kinetics.
Main Results:
- T315I mutant cells showed increased H2O2-induced mtDNA damage compared to sensitive cells.
- All cell lines exhibited decreased H2O2-induced mtDNA damage after repair incubation, significantly in sensitive and T315I cells.
- No significant differences were found in mtDNA copy number or the frequency of a specific 3,867-bp deletion across cell lines.
Conclusions:
- Mitochondrial DNA mutagenesis, particularly sensitivity to oxidative stress and DNA repair efficiency, contributes to imatinib resistance in CML.
- These findings highlight the potential of targeting mitochondrial pathways to overcome imatinib resistance.
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