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Mechanisms of resistance to tyrosin kinase inhibitors in treatment of patients with chronic myeloid leukemia The introduction of tyrosine kinase inhibitor (TKI) therapy represented a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). Despite a high success rate of the TKI therapy, 20-30 % of patients develop resistance to the treatment. The aim of this work was to study the mechanisms, related to the mutation development in BCR-ABL1 kinase domain (KD) or in the other genes responsible for TKI resistance, using the in vitro CML models. Furthermore, the effect of interferon alpha (IFN-α) and TKI sequential therapy on the presence of clones with multidrug-resistant mutations and a role of activation the immune response in achieving the treatment response were followed. Lastly, we studied the possibility of using the measurement of gene expression of hOCT1 and ABCB1 transporters at the time of diagnosis in CML patients as a predictive marker of the imatinib treatment response. KCL-22 CML cell line cells exposed to imatinib were repeatedly able to develop BCR-ABL1 kinase domain mutations. We demonstrated the existence of de novo mutagenesis in clones derived from the KCL-22 cell line. In four clones, which can proliferate in 4µM imatinib, mutations in BCR-ABL1 KD or KRAS were... |
