King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Int J Mol Sci. 2024 Mar 18;25(6):3419. doi: 10.3390/ijms25063419.
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 () 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 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 . Twenty-nine 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 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 have an impact on its structure and function. Thus, the annotation of SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.
急性髓系白血病 (AML) 的特征是髓样母细胞的克隆性增殖。编码 III 类受体酪氨酸激酶的 fms 样酪氨酸激酶 3 () 基因突变导致这种异质性血液恶性肿瘤显著相关。fms 相关酪氨酸激酶 3 配体与 FLT3 受体的细胞外结构域结合，在质膜中诱导同源二聚体形成，导致骨髓中造血细胞的凋亡、增殖和分化的自身磷酸化和激活。在本研究中，我们评估了 作为 AML 的重要生物标志物，并试图理解特定变异对 FLT3 蛋白结构和功能的影响。我们还使用分子对接研究了 I836 变异对与索拉非尼结合亲和力的影响。我们整合了多个生物信息学工具、数据库和资源，如 OncoDB、UniProt、COSMIC、UALCAN、PyMOL、ProSA、Missense3D、InterProScan、SIFT、PolyPhen 和 PredictSNP，以注释与 相关的已知变异对结构、功能和表型的影响。使用 DynaMut、CUPSAT、AutoDock 和 Discovery Studio 等计算方法分析了 29 个 变异，以评估其对蛋白质稳定性、灵活性、功能和结合亲和力的影响。OncoDB 和 UALCAN 门户证实了 基因表达及其突变状态与 AML 的关联。对 FLT3 中有害变异的计算结构分析表明，I863F 突变体使蛋白质结构不稳定，可能导致功能发生变化。FLT3 中的许多单核苷酸变异对其结构和功能有影响。因此，对 中的 SNV 进行注释，并预测其有害的致病性影响，将有助于深入了解肿瘤发生过程，并指导实验研究和临床应用。
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