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کاربرد نوع شرط:
- جایگاه : پژوهشی
- مجله: Asian Pacific Journal of Cancer Prevention
- نوع مقاله: Journal Article
- کلمات کلیدی: Chronic myeloid leukemia,tyrosine kinase inhibitors,Nilotinib,BCR-ABL Mutation
- چکیده:
- چکیده انگلیسی: Objective: BCR-ABL fusion oncogene is the hallmark of chronic myeloid leukemia (CML), causing genomic instability which leads to accumulation of mutations in BCR-ABL as well as other genes. BCR-ABL mutations are the cause of tyrosine kinase inhibitors (TKIs) resistance in CML. Recently, compound BCR-ABL mutations have been reported to resist all FDA approved TKIs. Therefore, finding novel compound BCR-ABL mutations can help and clinically manage CML. Therefore, our objective was to find out novel drug-resistant compound BCR-ABL mutations in CML and carry out their protein modelling studies. Methodology: Peripheral blood samples were collected from ten imatinib resistant CML patients receiving nilotinib treatment. BCR-ABL transcript mutations were investigated by employing capillary sequencing. Patient follow-up was carried out using European LeukemiaNet guidelines. Protein modeling studies were carried out for new compound mutations using PyMol to see the effects of mutations at structural level. Results: A novel compound mutation (K245N mutation along with G250W mutation) and previously known T351I utation was detected in two of the nilotinib resistance CML patients respectively while in the rest of 8 nilotinib responders, no resistant mutations were detected. Protein modelling studies indicated changes in BCR-ABL mutant protein which may have negatively impacted its binding with nilotinib leading to drug resistance. Conclusion: We report a novel nilotinib resistant BCR-ABL compound mutation (K245N along with G250W mutation) which impacts structural modification in BCR-ABL mutant protein leading to drug resistance. As compound mutations pose a new threat by causing resistance to all FDA approved tyrosine kinase inhibitors in BCR-ABL+ leukemias, our study opens a new direction for in vitro characterization of novel BCR-ABL compound mutations and their resistant to second generation and third generation TKIs.
- انتشار مقاله: 05-03-1399
- نویسندگان: Zafar Iqbal,Muhammad Absar,Amer Mahmood,Aamer Aleem,Mudassar Iqbal,Abid Jameel,Tanveer Akhtar,Sajjad Karim,Mahmood Rasool,Zeenat Mirza,Muhammad Khalid,Afia Muhammad Akram,Muhammad Farooq Sabar,Ahmad M Khalid,Khalid Aljarrah,Janhangir Iqbal,Muhammad Khalid,Ijaz H Shah,Nawaf Alanazi
- مشاهده