Format

Send to

Choose Destination
Acta Biochim Pol. 2016;63(2):365-70. doi: 10.18388/abp.2015_1189. Epub 2016 Jan 12.

Mitochondrial mutagenesis in BCR-ABL1-expressing cells sensitive and resistant to imatinib.

Author information

1
Department of Molecular Genetics, University of Lodz, Łódź, Poland.
2
Department of Flow Cytometry, Medical Center for Postgraduate Education, Warsaw, Poland.
3
Department of Infectious and Liver Diseases, Medical University of Lodz, Łódź, Poland.
4
Department of Orthodontics, Medical University of Lodz, Łódź, Poland.
5
Department of Microbiology and Immunology, School of Medicine, Temple University, Philadelphia, PA 19140, USA.

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.

PMID:
26757169
DOI:
10.18388/abp.2015_1189
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Acta Biochemica Polonica, Inc.
Loading ...
Support Center