الفهرس 
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Abstract
Introduction:. Despite the impressive outcome in the response to TKI, there is a proportion of patients that still have resistance to TKI and may go through advanced stage (AP/BC) of the disease. The aim of work: The aim of our study is to identify new molecular factors (BCR-ABL1 independent somatic mutations) that may play a role in development of resistance to tyrosine kinase inhibitor therapy in CML patients using next generation sequencing technique. Research Plan:. This study was carried out on 59 CML resistant patients divided into two cohorts; the first cohort included 16 patients in secondary resistance and they served as screening cohort for detection of somatic mutations by WES of matched paired samples. The second cohort used as a validation cohort on 43 CML resistant patients for deep sequencing with a panel of 18 genes, from which 10 were already detected in the screening cohort. Results: The ASXL1 and RUNX1 gene mutations were the most detected mutations in this study, mutation in ASXL1 gene showed a specific recurrent variant (p. G642fs) which was detected in 3 patients within our study, also in patients who had mutations in RUNX1 gene, there was 2 variants, each was detected in 2 patients (p. P425Q and p. G530A). Conclusion:. This study suggests that BCR-ABL1 independent somatic mutations play a role in the development of TKI resistance and disease progression to advanced stages, especially in resistant patients lacking BCR-ABL1 mutations.