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

Scientific Reports
Chodimella ChandrasekharPotukuchi Venkata Gurunadha Krishna Sarma

Abstract

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. Th...Continue Reading

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Citations

Apr 27, 2019·Molecular Biology Reports·Irina Cezara Vacarean-TrandafirDumitru Cojocaru
Jul 29, 2020·Proceedings of the National Academy of Sciences of the United States of America·Marc HoembergerDorothee Kern
May 7, 2020·International Journal of Molecular Sciences·Karol BukowskiRenata Kontek
Jun 21, 2020·Nature Reviews. Genetics·Ann Lin, Jason M Sheltzer

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MG641938
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electrophoresis
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