Browsing by Author "Ates, Onur"

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Lineage-Specific Transcriptomic Signatures and Therapeutic Target Discovery in Myeloid and Lymphoid Leukemias
(Taylor & Francis Ltd, 2025) Ozay, Basak; Ates, Onur; Kiraz, Yagmur
Aim: Leukemias are heterogenous hematologic malignancies broadly classified into myeloid and lymphoid lineages, each with distinct molecular and clinical features. Here we aime to identify lineage-specific molecular vulnerabilities in myeloid and lymphoid leukemias and use them to guide targeted therapy and rational drug repurposing. Materials & methods: A meta-analysis of 19 GEO datasets comprising >2,600 samples from acute and chronic leukemia subtypes was performed. Differentially expressed genes (DEGs) were identified and subjected to functional enrichment and protein-protein interaction (PPI) network analyses. Hub genes were identified for drug repurposing using the LINCS L1000CDS2. Candidate compounds were validated by performing molecular docking, dynamics simulations and MTT assays on multiple leukemia cell lines. Results: 269 DEGs in myeloid and 316 DEGs in lymphoid leukemias were identified. Enrichment analysis showed that DNA replication and cell cycle pathways drive myeloid leukemias, while lymphoid leukemias are associated with transcriptional regulation and immune signaling. Hub genes included CCNB1, KIF11, EGFR and JUN. SN-38 and C646 were identified as promising candidates from drug repurposing. Docking and molecular dynamics simulations confirmed strong binding to IGF1R and RBP2. MTT assays revealed significant, time- and dose-dependent cytotoxicity. Conclusion: This integrative approach links transcriptomics with drug discovery and preclinical validation. Lineage-specific vulnerabilities were uncovered, providing a framework for precision therapy and rational drug repurposing in leukemia.
Unraveling bortezomib resistance in multiple myeloma: insights from RNA-Seq and PI3K/mTOR pathway analysis
(Journal of Biological Research - Bollettino della Società Italiana di Biologia Sperimentale, 2026-01-04) Ates, Onur; Kiraz, Yagmur
Multiple Myeloma (MM), characterized by abnormal plasma cell proliferation, lacks curative treatment due to drug resistance, notably against Bortezomib, a critical proteasome inhibitor. To elucidate resistance mechanisms, we conducted RNA sequencing on Bortezomib-sensitive and resistant RPMI-8226 MM cells, comparing them to healthy B-cells. Differential expression analysis highlighted significant alterations in immune signaling, proteasome function, and metabolism. Resistant MM cells exhibited decreased antigen-presentation genes (HLA-DRA, HLA-DPA1, CD74), indicating immune evasion. Downregulation of metabolic regulators like GLUL and MDK suggested a glycolytic metabolic shift, whereas enhanced proteasome activities and nucleocytoplasmic transport represented adaptive strategies against proteotoxic stress. Importantly, resistant cells showed notable upregulation of PRAME and FAF1 genes, as oncogenes and apoptosis-related genes linked to therapy resistance. Pathway analysis revealed enrichment in neurodegenerative disease-related pathways, suggesting common protein misfolding mechanisms in MM progression. Additionally, resistant cells displayed cross-resistance to the dual protein kinase B (AKT)/mammalian target of rapamycin (mTOR) BEZ235, with a four-fold increase in IC₅₀ values, reflecting enhanced survival signaling and metabolic flexibility. These findings underscore the multifaceted nature of Bortezomib resistance, driven by metabolic reprogramming, immune modulation, and translational regulation. Targeting these adaptive pathways through combination therapies involving proteasome inhibitors, metabolic modulators, and autophagy inhibitors may present novel strategies to overcome drug resistance in MM.