Abstract
Highly polymorphic BCR-ABL kinase domains have been reported to harbor more than a hundred mutations, and among these, 40–60% have been identified as influencers of imatinib mesylate (IM) resistance. The emergence of IM resistance poses a significant challenge in the management of Chronic Myeloid Leukemia (CML). M351T (rs121913457), E255K (rs387906517), and Y253H (rs121913461) are of particular clinical significance due to their association with high-level imatinib resistance. This study was conducted to investigate the potential role of three significant SNPs in CML progression due to IM resistance. During the study period from 2018 to 2022 (48 months), the blood samples from 219 Reverse transcriptase-PCR-confirmed CML patients following RNA extraction and cDNA preparation were subjected to M351T, E255K, and Y253H mutation analysis by PCR–RFLP. After agarose gel visualization, the samples were subjected to Sanger sequencing to confirm the nucleotide change at the polymorphic loci. The wild-type genotype of all three ABL1 SNPs under investigation exhibits a significant reduction in frequency among IM non-responders compared to the responder group. The CGT haplotype frequency exhibits a significant difference between IM responder (4.2%) and non-responder (11.8%) (p = 0.002 < 0.05). Further, CGC haplotype was observed solely among the imatinib non-responder patients with a frequency percentage of 3.3% (p = 0.004), whereas the said genotype was absent among the responder group. A reduced overall survival rate was observed with deviation from wild-type genotype (M351T loci (T > C) with 1.217 times, E255K (G > A) with 1.485 and Y253H (T > C) with 1.399 times increase in hazard ratio) thereby enhancing mortality risk due to disease progression. The significant increase in the frequency of M351T, E255K, and Y253H loci among the IM non-responder group indicated their probable association with the development of IM resistance among CML patients. A haplotype frequency distribution pattern analysis of ABL1 loci further identified the CGC haplotype as an independent predictor for IM resistance. As such the study highlights the importance of patient characteristics, genotype distribution, and haplotype frequency distribution in predicting the response to IM treatment and clinical outcomes of CML patients.
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GH carried out the survey, samples collection, and execution of experiments. AR and GK monitor the works as Lab In-Charge, MGI and SM conceived and designed the experiments. GH, MJK, and LL critically analyzed the data and prepared the manuscript, SK, PPD, and KD helped in manuscript writing. VK guided in clinical data analysis.
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This study was approved by the Institutional Ethics Committee of Assam Medical College Hospital, Dibrugarh, Assam No AMC/EC/1594 dated 24/7/2020 and Gauhati University Ethics Committee, Guwahati, Assam No: GUIEC/2021/019 dated: 29/9/2021.
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Hazarika, G., Kalita, M.J., Das, P.P. et al. Occurrence of Existing BCR-ABL Baseline Mutations and Associated Haplotype (NmR) Among CML Patients with Diverse IM Response: A Hospital-based Study from North-East India. Biochem Genet (2024). https://doi.org/10.1007/s10528-024-10676-x
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DOI: https://doi.org/10.1007/s10528-024-10676-x