Browsing by Author "Kiraz, Yagmur"

Now showing 1 - 5 of 5

Determination of Survival Associated Genetic Biomarkers To Discover Novel Therapeutic Targets for Acute Myeloid Leukaemia
(Taylor & Francis Ltd, 2025) Ergun, Cansu; Kiraz, Yagmur; Ayna Duran, Gizem
Acute myeloid leukemia (AML) is a heterogeneous malignancy specified by clonal proliferation of hematopoietic stem cells. This study identifies novel therapeutics for AML by integrating differential gene expression (DEG) and survival analyses. Publicly available GEO microarray datasets were analyzed, including data from 615 AML patients and 22 healthy controls. Multivariate Cox regression identified hazardous genes impacting survival. Protein-protein interaction networks using CytoScape revealed hub genes such as CCT5, ZBTB16, APP, and PTPN6. Functional enrichment revealed key AML-related pathways, such as PI3K/Akt and NF-kappaB signaling. Drug repurposing using the LINCS L1000CDS2 database highlighted potential therapeutics, including 16-Hydroxytriptolide and Tryptosthin AG-1478, with roles in reversing hazardous gene expression patterns. Additional candidates such as Vemurafenib, Parthenolide and Wortmannin, demonstrated promise as targeted agents. These findings underscore the potential of integrating bioinformatics and drug discovery to identify precision medicine in AML. Further studies are warranted to validate these targets and explore their clinical utility.
In Silico Approach for Identification of PI3K/MTOR Dual Inhibitors for Multiple Myeloma Treatment
(Istanbul Univ, 2023) Masalaci, Ilke; Akdogan, Yaren; Mutlu, Ozge; Eyvaz, Hande; Kiraz, Yagmur
Objective: Multiple myeloma is a hematologic malignancy in which targeting phosphoinositide 3 kinase (PI3K) and/or the mammalian target of rapamycin (mTOR) individually has been shown to have anti-proliferative effects, however, inhibiting both proteins simultaneously has been reported to have more effective results for its treatment. The aim of this study is to determine the molecular interactions and predicted inhibitory effects of 40 different dual inhibitors on mTOR, PI3K delta, and PI3K gamma to propose potentially the most effective dual inhibitor that targets the PI3K delta and PI3K gamma isoforms as well as the mTOR proteins since those isoforms are known to be predominant in multiple myeloma patients. Therefore, the focus in this study is built around the specific targeting of the PI3K delta and PI3K gamma isoforms from the multiple myeloma perspective. Materials and Methods: In silico docking experiments were conducted to determine the binding energies for different ligands that target mTOR, PI3K delta, and PI3K gamma. Protein-dual inhibitor complexes and the amino acids and bond types were visualized to identify molecular interactions. The absorption, distribution, metabolism, and excretion properties of dual inhibitors were analyzed and evaluated. Results: The binding affinity values were found to be between -7 and -9.9 kcal/mol. The toxicity prediction values of the selected dual inhibitors were obtained from the Pro-Tox-II web tool and classified according to the globally harmonized system of classification of labeling of chemicals. Conclusion: Correspondingly, among all dual inhibitors, Vistusertib is determined to be a promising compound against multiple myeloma cells by inhibiting both PI3K delta and PI3K gamma as well as mTORC1/2.
LEP and FOXO1 Genes, as a Proposed Tumor Suppressor Autophagic Cell Death Related Genes, Can Be Targeted by Antidiabetic Therapy in Nondiabetic Breast Cancer Patients
(Springer, 2025) Duran, Gizem Ayna; Kiraz, Yagmur; Baykara, Deniz
Introduction Breast cancer can be treated effectively with personalized, gene-targeted therapies due to its molecular and genetic differences. Our study aims to identify breast cancer-specific tumor suppressor genes related to autophagic cell death and discover new drugs that target these mechanisms, even if they are not breast cancer-specific. Materials and methods Gene intensity values of 457 tumor and 19 healthy breast tissues were used to determine downregulated and upregulated genes related to autophagy and apoptosis using Bioconductor R program via LIMMA package. Then, genes affecting survival were identified by survival analysis via Kaplan-Meier Plotter tool. Furthermore, the signalling pathways associated with these genes and targeting candidate drug components were determined by gene enrichment analysis using "KEGG pathway option" and Drug MATADOR in "ShinyGo 0.82" web-tool, respectively. Results Breast cancer tumor tissues showed downregulation of genes related to autophagy and apoptosis (c19orf12, CRYAB, LEP, SRPX, SNCA, FOXO1) and upregulation of others (SLC7A5, ATP2A2, INHBA, ATP5IF1). Among these, SLC7A5, c19orf12, LEP, SPRX, SNCA, and FOXO1 affected patient survival and prognosis. The AMPK signaling pathway, targeting FOXO1 and LEP, was identified as key. Only the LEP gene was targeted by Metformin, Pioglitazone, Rosiglitazone, and Troglitazone. Conclusion In our study, survival associated LEP and FOXO1 genes were identified as candidate tumor suppressor genes associated with autophagic cell death in non-obese and non-diabetic breast cancer patients. Anti-diabetic drugs such as Metformin, Pioglitazone, Rosiglitazone, Troglitazone are proposed as candidate components in the treatment processes by targeting the LEP gene in nondiabetic breast cancer patients.
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.