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Landscape of FLT3 Variations Associated with Structural and Functional Impact on Acute Myeloid Leukemia: A
Zeenat Mirza1,2, Dalal A Al-Saedi3, Nofe Alganmi4,5
1King Fahd Medical Research Center, 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.
Insights
Mutations in the fms-like tyrosine kinase 3 (FLT3) gene are linked to acute myeloid leukemia (AML). This study analyzes FLT3 variants, predicting their impact on protein structure and function to aid AML research and treatment.
Area of Science:
- Hematology
- Molecular Biology
- Bioinformatics
- Oncology
Background:
- Acute myeloid leukemia (AML) is characterized by the uncontrolled growth of myeloid blasts.
- Mutations in the fms-like tyrosine kinase 3 (FLT3) gene are frequently observed in AML and are associated with poor prognosis.
- FLT3 signaling pathways regulate hematopoietic cell development, and aberrant activation contributes to leukemogenesis.
Purpose of the Study:
- To investigate the role of FLT3 gene variations as biomarkers in AML.
- To understand the structural and functional consequences of specific FLT3 mutations.
- To evaluate the impact of FLT3 variants on binding affinity to the drug sorafenib using molecular docking.
Main Methods:
- Integrated multiple bioinformatics tools and databases (OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, PredictSNP).
- Analyzed 29 FLT3 variants using in silico approaches (DynaMut, CUPSAT, AutoDock, Discovery Studio) to assess protein stability, flexibility, function, and binding affinity.
- Performed computational structural analysis and molecular docking studies.
Main Results:
- Confirmed the association of FLT3 gene expression and mutational status with AML using OncoDB and UALCAN.
- Identified I863F FLT3 mutants as destabilizers of protein structure, potentially altering function.
- Demonstrated that numerous single-nucleotide variations in FLT3 significantly impact its structure and function.
Conclusions:
- FLT3 variants play a crucial role in AML pathogenesis.
- In silico annotation and prediction of deleterious FLT3 single-nucleotide variants provide insights into tumorigenesis.
- Findings can guide future experimental studies and clinical applications for AML treatment.
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