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

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.