Novel mutations in the kinase domain of BCR-ABL gene causing imatinib resistance in chronic myeloid leukemia patients

Mutations in the drug binding region of BCR-ABL lead to imatinib resistance during the management of chronic myeloid leukemia (CML). In our study, 62 Philadelphia positive (Ph(+)) CML patients showing conspicuous expression of BCR-ABL gene were treated with imatinib. At the end of 3 months, 21/62 (33.87%) patients did not obtain complete hematological response (CHR) and also showed no significant decrease in BCR-ABL gene expression. In all the imatinib-resistant patients BCR-ABL gene was PCR amplified and sequenced. The sequence analysis showed four novel missense mutations p.(Leu301Ile), p.(Tyr320His), p.(Glu373Asp), p.(Asp381Asn) and six already reported mutations p.(Val256Gly), p.(Thr315Ile), p.(Gly250Glu), p.(Tyr253His), p.(Phe317Leu), p.(Met351Thr) which contributed in the formation of inactive enzyme and also two novel frameshift mutations p.(Glu281*) and p.(Tyr393*), which resulted in truncated protein formation. Further, the structural analysis revealed all these mutations affected P-loop, gatekeeper, catalytic and activation loop domain regions of the enzyme causing poor imatinib binding in the ATP region. The primary intention of the study was to find out the mutations in the BCR-ABL gene causing imatinib resistance. This study highlights the need for BCR-ABL gene sequence analysis to detect the mutations in CML patients in order to properly guide the therapy.