Abstract
Abstract Diffuse large B-cell lymphomas (DLBCL) harbor recurrent abnormalities in epigenetic regulators, such as loss-of-function mutations in EP300 and CREBBP. These include gain-of-function mutations in EZH2, largely restricted to the germinal center B-Cell (GCB) subtype. An EZH2 inhibitor EPZ-6438 showed efficacy as a single agent in phase I clinical trials in relapsed/refractory GCB-DLBCL. We examined the effect of EZH2 inhibition in GCB-DLBCL cell lines, and found an increase in histone arginine methylation in surviving cells, which was attributable to increased Type I PRMT activity. Specifically, we discovered that EZH2 inhibitors activated PRMT1, which mediated protective effects through transcriptional changes at survival genes such as BCL2, and through modulation of B-cell receptor signaling. This exciting observation suggested an opportunity for combination therapy with PRMT1 inhibitors. Since PRMT1 is poorly studied in DLBCL, we performed single-agent studies in lymphoma cell lines and discovered that inhibition of PRMT1 elicited remarkable suppression of lymphoma cell growth and viability. Analysis of gene expression data from patients indicates that PRMT1 is overexpressed in untreated DLBCL tumor samples, compared to normal B-lymphocytes. Additionally, survival analysis revealed that patients with high PRMT1 expression showed poor overall survival. These observations support the potential for combinatorial treatment with EZH2 and PRMT1 inhibitors in patients. To summarize, our studies uncover a novel epigenetic target in DLBCL, and offer avenues for improving the antitumor efficacy of EZH2 inhibitors. Citation Format: Aarthi Goverdhan, Heng-Huan Lee, Ondrej Havranek, Richard Eric Davis, Mien-Chie Hung. PRMT1 as a therapeutic target in diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 13.
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