|
Document Type |
: |
Thesis |
|
Document Title |
: |
Mutations associated with BCR-ABL TKI resistance in CML patients الطفرات المرتبطة بمقاومة BCR-ABL TKI في مرضى سرطان الدم النخاعي المزمن |
|
Subject |
: |
Faculty of Applied Medical Sciences |
|
Document Language |
: |
Arabic |
|
Abstract |
: |
Background: Targeted therapy via tyrosine kinase inhibitors (TKI) has improved the management and the outcome of CML patients in the past decade, nevertheless not all CML patients experience an optimum TKI response. Moving on, various studies evidenced the association between CML TKI-resistance and mutations in the kinase domain (KD) of BCR-ABL, yet most of these studies cannot explain 20–40% of TKI-resistance cases. Due to the lack of studies investigating the deep genetic profiles of the CML patient associated with TKI-resistance, this study was aiming to investigate the genetic profile underlying BCR-ABL chronic myeloid leukemia TKI-resistance in Saudi Arabian patients.
Materials and methods: For this study, we analyzed genetic DNA profile of 3 CML TKI-resistance cases in 3 different stages of the disease, 3 samples at diagnostic stage, 3 samples at remission stage and 3 sample at relapse stage. Furthermore, for control samples, we analyzed 2 different control samples, 2 healthy control samples and a cured CML samples at 2 stages (diagnostic stage and remission stage). All the samples were analyzed using a next-generation sequencing platform (illumina trusight one expanded panel), annotated via software program VariantStudio™ 3.0 with an in-house filtration pipeline.
Results: Our study indicate that only 2 genes where found to be interesting, IGSF3 (NM_001542.3:c.1169T>C) and IGF2 (NM_001127598.1:c.671A>C) with unique missense variants that were consisted in all the cases and persisted during the three stages (diagnosis, remission and relapse). The function of IGSF3 gene is largely unknown but possibly associated to the TKI resistance cases through the NF-κB pathway. The IGF2 stimulates proliferation and activation of tyrosine kinase signaling pathway through binding to IGFBP-1. Both IGSF3 and IGF2 mutations are novel variants which was not reported before in accusation with CML TKI resistance cases.
Conclusion: Despite the small size of this study, this is one of the first NGS studies that associate CML TKI-resistance cases to clinically relevant mutations thus aiding for more effective targeted therapies. This study recommends further validation and investigation on a larger cohort to identify the pathogenicity of theses abnormality. |
|
Supervisor |
: |
Dr. Heba A AL-Khatabi |
|
Thesis Type |
: |
Master Thesis |
|
Publishing Year |
: |
1442 AH
2021 AD |
|
Co-Supervisor |
: |
Prof. Adel M. Abuzinadah |
|
Added Date |
: |
Monday, September 20, 2021 |
|
Researchers
| مرام عمار امين | Amin, Maram Ammar | Researcher | Master | |
|