Author ORCID Identifier

0000-0002-7879-7748

Date of Graduation

8-2017

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mien-Chie Hung, Ph.D.

Committee Member

Mark T. Bedford, Ph.D.

Committee Member

Paul J. Chiao, Ph.D.

Committee Member

Richard E. Davis, M.D.

Committee Member

Min Gyu Lee, Ph.D.

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.

Keywords

Lymphoma, epigenetics, methyltransferases, EZH2, PRMT1

Available for download on Saturday, July 28, 2018

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