%0 Journal Article %T Discovery and Protein Modeling Studies of Novel Compound Mutations Causing Resistance to Multiple Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia %J Asian Pacific Journal of Cancer Prevention %I West Asia Organization for Cancer Prevention (WAOCP), APOCP's West Asia Chapter. %Z 1513-7368 %A Iqbal, Zafar %A Absar, Muhammad %A Mahmood, Amer %A Aleem, Aamer %A Iqbal, Mudassar %A Jameel, Abid %A Akhtar, Tanveer %A Karim, Sajjad %A Rasool, Mahmood %A Mirza, Zeenat %A Khalid, Muhammad %A Akram, Afia Muhammad %A Sabar, Muhammad Farooq %A Khalid, Ahmad M %A Aljarrah, Khalid %A Iqbal, Janhangir %A Khalid, Muhammad %A Shah, Ijaz H %A Alanazi, Nawaf %D 2020 %\ 12/01/2020 %V 21 %N 12 %P 3517-3526 %! Discovery and Protein Modeling Studies of Novel Compound Mutations Causing Resistance to Multiple Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia %K Nilotinib %K BCR-ABL Mutation %K Chronic myeloid leukemia %K tyrosine kinase inhibitors %R 10.31557/APJCP.2020.21.12.3517 %X 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 modelingĀ  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 secondĀ  generation and third generation TKIs. %U https://journal.waocp.org/article_89386_d77fec02bb6fa34f9a228b048dd34c04.pdf