An FDA-approved HDAC inhibitor for B-cell lymphoma is currently not available. While pan-HDAC inhibitors (HDIs) hold much promise, they display unwanted toxic side effects, because they hit multiple enzymes belonging to both Class I and/or Class II HDAC families. Class I HDAC (HDAC 1, 2, 3, and 8) are the key targets of many pan-HDIs, including the FDA-approved drugs SAHA and depsipeptide. Diffuse large B-cell lymphoma (DLBCL), a type of non-Hodgkin's lymphoma, is the most common lymphoid malignancy of all adult lymphomas. These lymphoma cells acquire chemoresistance and consequently have a high relapse rate, making it a hard-to-treat disease. About 30% of germinal center (GC)-derived DLBCLs have a recurrent somatic gain-of-function mutation (GOF) in the polycomb-group oncogene EZH2. EZH2 codes for the methyltransferase that catalyzes histone H3 lysine-27 trimethylation (H3K27me3) and promotes lymphomagenesis. Increased levels of EZH2 are purported to also contribute to chemoresistance in EZH2GOF DLBCL cells. EZH2-catalyzed H3K27me3 localizes to double-strand breaks (DSBs) and participates in DNA repair. Our published and recent unpublished results showed that selective inhibition of HDAC1,2 decreases H3K27me3 at DSBs during DSB repair, alters the H3K27me3/H3K27ac switch specifically at DSB sites, and impairs EZH2-mediated downstream repair signaling. In addition to H3K27me3, we found that EZH2GOF DLBCL cells overexpress B-lymphoma and BAL-associated protein (BBAP) enzyme that also confers chemoresistance to EZH2GOF DLBCL cells. BBAP is an E3 ubiquitin ligase and catalyzes H4K91ub1, which is also involved in DNA repair. Our published results showed that selective inhibition of HDAC1,2 decreases H3K27me3 at DSBs and H4K91ub1 during DSB repair by increasing H3K27ac and H4K91ac. This alteration of H3K27me3/H3K27ac and H4K91ub1/H4K91ac switches results in decreased DSB repair, an induction of DNA damage response, and cytotoxic effects, providing a novel mechanism by which HDAC1,2 inhibition can overcome survival advantage in chemoresistant DLBCL cells. The consequences of the altered H3K27me3/H3K27ac switch on DNA repair events are still not understood. How HDAC1,2 acts in concert with enzymes that modulate the chromatin dynamics during DSB repair in EZH2GOF DLBCL is not clear. We hypothesize that HDAC1,2 inhibition specifically impairs DSB repair used by EZH2GOF DLBCL cells at various steps (local transcriptional repression at DSBs during active repair and the chromatin remodeling required for DNA repair). We will present our recent results obtained from the mechanistic studies performed to address the above-mentioned questions. We are also investigating how HDAC1,2 functions in normal germinal center functions to complement our lymphoma studies.

Citation Format: Danielle Johnson, Sneha Patel, Srividya Bhaskara. Targeting DNA repair in EZH2 gain-of-function diffuse large B-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-43.