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.
Highlights
The BCR-ABL1 oncogene results from the t(9;22) (q34;q11) reciprocal translocation leading to a fusion of a part of the BCR gene on chromosome 9 with the ABL1 gene on chromosome 22.1 The product of BCRABL1 expression, the BCR-ABL1 protein, has enhanced tyrosine kinase activity, activates several signaling pathways, and confers growth and proliferation advantages, which are typical for cancer cells.[2]
BCR-ABL1 is a hallmark of chronic myeloid leukemia (CML), which therapy has been revolutionized by imatinib, a tyrosine kinase inhibitor (TKI), which has changed CML from a fatal disorder into a chronic disease.[1]
We previously showed that BCR-ABL1 induced reactive oxygen species (ROS) that might contribute to imatinib resistance.[8]
Summary
BCR-ABL1 is a hallmark of chronic myeloid leukemia (CML), which therapy has been revolutionized by imatinib, a tyrosine kinase inhibitor (TKI), which has changed CML from a fatal disorder into a chronic disease.[1] Imatinib binds the adenosine triphosphate (ATP)-binding pocket in BCR/ABL1, inhibiting its kinase activity by blocking its binding by ATP, its cofactor. Resistance to imatinib has become an emerging problem in CML therapy, which is only partly resolved by second and third generations of TKIs.[3].
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