Affiliation:
1. King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
2. Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
3. Department of Biochemistry, Faculty of Sciences, University of Tabuk, Tabuk 48322, Saudi Arabia
4. Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia
5. Computer Science Department, Faculty of Computing and Information Technology, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Abstract
Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein’s structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3. Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.
Funder
Ministry of Education and King Abdulaziz University, Jeddah, Saudi Arabia
Reference68 articles.
1. Durable remission of acute myeloid leukemia in an elderly patient following a limited course of azacitidine and venetoclax;Ehsan;Leuk. Res. Rep.,2022
2. Pediatric AML: From Biology to Clinical Management;Zwaan;J. Clin. Med.,2015
3. (2024, February 24). Leukemia—Acute Myeloid—AML: Statistics. Available online: https://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/statistics#:~:text=The%205%2Dyear%20relative%20survival%20rate%20for%20people%2020%20and,well%20the%20treatment%20plan%20works.
4. Comorbidity, age, and mortality among adults treated intensively for acute myeloid leukemia (AML);Tawfik;J. Geriatr. Oncol.,2016
5. Successes and challenges in the treatment of pediatric acute myeloid leukemia: A retrospective analysis of the AML-BFM trials from 1987 to 2012;Rasche;Leukemia,2018
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献