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Exploring Prognostic Biomarkers of Acute Myeloid Leukemia to Determine Its Most Effective Drugs from the FDA-Approved
Md Murshid Alom1, Md Omar Faruqe2, Md Khademul Islam Molla2
1Laboratory of Molecular Health Science, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh.
Abstract:
Acute myeloid leukemia (AML) is a blood cancer caused by the abnormal proliferation and differentiation of hematopoietic stem cells in the bone marrow. The actual genetic markers and molecular mechanisms of AML prognosis are unclear till today. This study used bioinformatics approaches for identifying hub genes and pathways associated with AML development to uncover potential molecular mechanisms. The expression profiles of RNA-Seq datasets, GSE68925 and GSE183817, were retrieved from the Gene Expression Omnibus (GEO) database. These two datasets were analyzed by GREIN to obtain differentially expressed genes (DEGs), which were used for performing the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, protein-protein interaction (PPI), and survival analysis. The molecular docking and dynamic simulation were performed to identify the most effective drug/s for AML from the drug list approved by the Food and Drug Administration (FDA). By integrating the two datasets, 238 DEGs were identified as likely to be affected by AML progression. GO enrichment analyses exhibited that the upregulated genes were mainly associated with inflammatory response (BP) and extracellular region (CC). The downregulated DEGs were involved in the T-cell receptor signalling pathway (BP), an integral component of the lumenal side of the endoplasmic reticulum membrane (CC) and peptide antigen binding (MF). The pathway enrichment analysis showed that the upregulated DEGs were mainly associated with the T-cell receptor signalling pathway. Among the top 15 hub genes, the expression levels of ALDH1A1 and CFD were associated with the prognosis of AML. Four FDA-approved drugs were selected, and a top-ranked drug was identified for each biomarker through molecular docking studies. The top-ranked drugs were further confirmed by molecular dynamic simulation that revealed their binding stability and confirmed their stable performance. Therefore, the drug compounds, enasidenib and gilteritinib, can be recommended as the most effective drugs against the ALDH1A1 and CFD proteins, respectively.
