University of Texas Health Science Center at Houston
Targeting Epigenetic Regulators For The Treatment of Diffuse Large B-Cell Lymphoma
Abstract
dc:description.abstract<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>
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation (PhD)
- Year dc:date.available
- 2017
Author and committee
dc:creator, dc:contributor.*- Authors dc:creator
-
- Goverdhan, Aarthi
- <p><a href="http://orcid.org/0000-0002-7879-7748" target="_blank">0000-0002-7879-7748</a></p>
- Contributors dc:contributor
-
- Mien-Chie Hung, Ph.D.
- Mark T. Bedford, Ph.D.
- Paul J. Chiao, Ph.D.
Subjects
dc:subject × 6Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/787
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1829