Ismail, Nor Hayati (2024) Dysregulation of transcriptomic profiles of mm1.s and u266 multiple myeloma cell lines treated with epigenetic inhibitors. PhD thesis, Universiti Sains Malaysia.
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Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the uncontrolled proliferation of plasma cells in the bone marrow. Epigenetic dysregulation plays a pivotal role in MM pathogenesis, making epigenetic inhibitors promising therapeutic targets. This study examines the effects of three epigenetic inhibitors—Trichostatin A (TSA), Panobinostat (PAN), and 5-azacytidine (5-AZA) on MM1.S and U266 cell lines, focusing on transcriptomic dysregulation and the identification of core genes associated with survival outcomes. Dose-response curves revealed that all three inhibitors inhibited cell proliferation in a dose-dependent manner, with PAN showing the most potent anti-proliferative effect at the half maximal inhibitory concentration (IC50) dose. Flow cytometry analysis indicated significant changes in cell cycle distribution upon treatment. TSA, PAN, and 5-AZA induced G0/G1 phase arrest, suppression in S phase and no changes observed in G2/M phase in MM1.S cells and U266 cells. Apoptosis assays demonstrated that MM1.S cell lines experienced late apoptosis with the highest impact induced by PAN. Meanwhile, U266 cell lines demonstrated early apoptosis event after treatment with epigenetic inhibitors and the most profound impact induced by 5-AZA. KEGG enrichment analysis of both MM cell lines treated with these epigenetic inhibitors identified significant pathways involving cell adhesion molecules, microRNAs in cancer, and viral protein interactions with cytokines and receptors. Notably, this study also demonstrated that PAN and 5-AZA treatments upregulated certain core histone genes (H2A, H2B, H3, H4), co-impacting chromatin structure and gene regulation, thus influencing cellular processes and therapeutic responses. Furthermore, Kaplan-Meier plot analysis revealed that core genes linked to transcriptomic dysregulation were significantly associated with improved overall survival (OS) outcomes. The highest number of survival-associated core genes was found in 5-AZA-treated cell lines. Specifically, 5-AZA treatment increased the expression of similar core genes in both MM1.S and U266 cells, downregulating KIF20A, KIF4A, and PLK1, which correlated significantly with improved OS rate (log-rank P: 1.4e-16). In PAN-treated MM cell lines, ORC1, MCM2, MCM5, and CXCL1 were identified as core genes with therapeutic potential. TSA-treated U266 cell lines revealed more significant core genes than MM1.S cell lines, with APOE emerging as a key gene linked to improved survival outcomes (log-rank P < 1e-16). Overall, this study provides comprehensive insights into the transcriptomic alterations induced by epigenetic inhibitors in MM cell lines. These findings enhance the understanding of MM pathogenesis and offer potential therapeutic targets for treating this challenging disease.
| Item Type: | Thesis (PhD) |
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| Uncontrolled Keywords: | myeloma cell lines |
| Subjects: | R Medicine R Medicine > RC Internal medicine > RC254-282 Neoplasms. Tumors. Oncology (including Cancer) |
| Divisions: | Kampus Kesihatan (Health Campus) > Pusat Pengajian Sains Kesihatan (School of Health Sciences) > Thesis |
| Depositing User: | Mr Abdul Hadi Mohammad |
| Date Deposited: | 17 Feb 2025 08:32 |
| Last Modified: | 12 Mar 2025 07:46 |
| URI: | http://eprints.usm.my/id/eprint/61802 |
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