Small-molecule inhibitors of the histone methyltransferase EZH2 hold great promise for the treatment of Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL). Compared to a 60% Objective Response Rate (ORR) in Phase I clinical trials, Phase II trial results for the EZH2 inhibitor EPZ-6438 reported an attenuation of response. Mechanisms contributing to lymphoma cell survival and growth after EZH2 ablation are poorly studied. In EZH2-mutant cells, we found that B-Cell Receptor (BCR) signaling was enhanced after EZH2 inhibitor treatment, and associated with an activated B-cell phenotype. Genetic manipulation of BCR, CD19 and CD79A greatly increased sensitivity to the EZH2 inhibitor EPZ-6438. Combination therapy with SYK, PI3Kdelta and BTK kinase inhibitors was highly synergistic in multiple lymphoma cell lines, regardless of EZH2 mutation status. At the epigenetic level, prolonged treatment with EPZ-6438 increased global levels of Histone H4 Arginine-3 asymmetric di-methylation. In a subset of lymphoma cell lines, combination therapy with EZH2 and Type I PRMT inhibitors showed synergy. Interestingly, Type I PRMT inhibitors were also highly effective as a single-agent, and mediated apoptosis in lymphoma cells by transcriptionally down-regulating the anti-apoptotic protein BCL2. To summarize, we have identified ways to improve EZH2 inhibitor sensitivity in DLBCL cells and revealed a critical role for the arginine methyltransferase PRMT1 in the regulation of lymphoma growth and survival. Therefore, PRMT1 presents a novel and promising target for the treatment of this cancer type.
","abstract_html":"<p>Small-molecule inhibitors of the histone methyltransferase EZH2 hold great promise for the treatment of Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL). Compared to a 60% Objective Response Rate (ORR) in Phase I clinical trials, Phase II trial results for the EZH2 inhibitor EPZ-6438 reported an attenuation of response. Mechanisms contributing to lymphoma cell survival and growth after EZH2 ablation are poorly studied. In EZH2-mutant cells, we found that B-Cell Receptor (BCR) signaling was enhanced after EZH2 inhibitor treatment, and associated with an activated B-cell phenotype. Genetic manipulation of BCR, CD19 and CD79A greatly increased sensitivity to the EZH2 inhibitor EPZ-6438. Combination therapy with SYK, PI3Kdelta and BTK kinase inhibitors was highly synergistic in multiple lymphoma cell lines, regardless of EZH2 mutation status. At the epigenetic level, prolonged treatment with EPZ-6438 increased global levels of Histone H4 Arginine-3 asymmetric di-methylation. In a subset of lymphoma cell lines, combination therapy with EZH2 and Type I PRMT inhibitors showed synergy. Interestingly, Type I PRMT inhibitors were also highly effective as a single-agent, and mediated apoptosis in lymphoma cells by transcriptionally down-regulating the anti-apoptotic protein BCL2. To summarize, we have identified ways to improve EZH2 inhibitor sensitivity in DLBCL cells and revealed a critical role for the arginine methyltransferase PRMT1 in the regulation of lymphoma growth and survival. Therefore, PRMT1 presents a novel and promising target for the treatment of this cancer type.</p>","abstract_has_math":false,"creators":["Goverdhan, Aarthi",""],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Mien-Chie Hung, Ph.D.","Mark T. Bedford, Ph.D.","Paul J. Chiao, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2017,"date_issued":"2017-08-01T07:00:00Z","date_published":"2017-08-01T07:00:00Z","updated_at":"2026-07-24T05:50:16Z","subjects":["Lymphoma","epigenetics","methyltransferases","EZH2","PRMT1","Medicine and Health Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/787","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Mien-Chie Hung, Ph.D.","Mark T. Bedford, Ph.D.","Paul J. 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Compared to a 60% Objective Response Rate (ORR) in Phase I clinical trials, Phase II trial results for the EZH2 inhibitor EPZ-6438 reported an attenuation of response. Mechanisms contributing to lymphoma cell survival and growth after EZH2 ablation are poorly studied. In EZH2-mutant cells, we found that B-Cell Receptor (BCR) signaling was enhanced after EZH2 inhibitor treatment, and associated with an activated B-cell phenotype. Genetic manipulation of BCR, CD19 and CD79A greatly increased sensitivity to the EZH2 inhibitor EPZ-6438. Combination therapy with SYK, PI3Kdelta and BTK kinase inhibitors was highly synergistic in multiple lymphoma cell lines, regardless of EZH2 mutation status. At the epigenetic level, prolonged treatment with EPZ-6438 increased global levels of Histone H4 Arginine-3 asymmetric di-methylation. In a subset of lymphoma cell lines, combination therapy with EZH2 and Type I PRMT inhibitors showed synergy. Interestingly, Type I PRMT inhibitors were also highly effective as a single-agent, and mediated apoptosis in lymphoma cells by transcriptionally down-regulating the anti-apoptotic protein BCL2. To summarize, we have identified ways to improve EZH2 inhibitor sensitivity in DLBCL cells and revealed a critical role for the arginine methyltransferase PRMT1 in the regulation of lymphoma growth and survival. Therefore, PRMT1 presents a novel and promising target for the treatment of this cancer type.
"]},{"key":"dc:title","label":"Title","values":["Targeting Epigenetic Regulators For The Treatment of Diffuse Large B-Cell Lymphoma"]}]}],"canonical_facts":{"dc:contributor":["Mien-Chie Hung, Ph.D.","Mark T. Bedford, Ph.D.","Paul J. Chiao, Ph.D."],"dc:creator":["Goverdhan, Aarthi",""],"dc:date.available":["2021-07-28T07:00:00Z"],"dc:description.abstract":["Small-molecule inhibitors of the histone methyltransferase EZH2 hold great promise for the treatment of Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL). Compared to a 60% Objective Response Rate (ORR) in Phase I clinical trials, Phase II trial results for the EZH2 inhibitor EPZ-6438 reported an attenuation of response. Mechanisms contributing to lymphoma cell survival and growth after EZH2 ablation are poorly studied. In EZH2-mutant cells, we found that B-Cell Receptor (BCR) signaling was enhanced after EZH2 inhibitor treatment, and associated with an activated B-cell phenotype. Genetic manipulation of BCR, CD19 and CD79A greatly increased sensitivity to the EZH2 inhibitor EPZ-6438. Combination therapy with SYK, PI3Kdelta and BTK kinase inhibitors was highly synergistic in multiple lymphoma cell lines, regardless of EZH2 mutation status. At the epigenetic level, prolonged treatment with EPZ-6438 increased global levels of Histone H4 Arginine-3 asymmetric di-methylation. In a subset of lymphoma cell lines, combination therapy with EZH2 and Type I PRMT inhibitors showed synergy. Interestingly, Type I PRMT inhibitors were also highly effective as a single-agent, and mediated apoptosis in lymphoma cells by transcriptionally down-regulating the anti-apoptotic protein BCL2. To summarize, we have identified ways to improve EZH2 inhibitor sensitivity in DLBCL cells and revealed a critical role for the arginine methyltransferase PRMT1 in the regulation of lymphoma growth and survival. Therefore, PRMT1 presents a novel and promising target for the treatment of this cancer type.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/787"],"dc:subject":["Lymphoma","epigenetics","methyltransferases","EZH2","PRMT1","Medicine and Health Sciences"],"dc:title":["Targeting Epigenetic Regulators For The Treatment of Diffuse Large B-Cell Lymphoma"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:16Z"}