Genomic profiling of imatinib resistant and sensitive K562 cells to obtain insights into imatinib resistance
Chronic myeloid leukemia (CML) epitomizes successful targeted therapy, with 86% of patients in the chronic phase treated with tyrosine kinase inhibitors (TKIs) attaining remission. However, resistance to TKIs occurs during treatment, and patients with resistance to TKIs progress to the acute phase called Blast Crisis (BC), wherein the survival is restricted to 7-11 months. About 80 % of patients in BC are unresponsive to TKIs. This issue can be addressed by identifying a molecular signature which can predict resistance in CML-CP prior to treatment as well as by delineating the molecular mechanism underlying resistance. Herein, we report genomic analysis of CML patients and imatinib-resistant K562 cell line to achieve the same. WGS was performed on imatinib-sensitive and -resistant K562 cells. Library preparation was done by 30x WGS KAPA PCR-Free v2.1 kit, and Illumina HiSeq X sequencer was used for 2 x 150 bp paired-end sequencing. Our study identified accumulation of aberrations on chromosomes 1, 3, 7, 16 and 22 as predictive of occurrence of resistance. Further, recurrent amplification in chromosomal region 8q11.2-12.1 was detected in highly resistant K562 cells as well as  CML patients. The genes present in this region were analyzed to understand molecular mechanism of imatinib resistance.