Abstract 2348: BRD4 regulates the expression of Livin and thereby confers resistance to Fas-mediated immune cytotoxicity in aggressive B-cell lymphoma
Authors: Eiji Sugihara , Hashimoto Norisato , Osuka Satoru , Ueno Sayaka , Shimizu Takatsune , Okazaki Shogo , Sato Taka-aki , Okamoto Shinichiro , Saya Hideyuki 
Published: August 2019

Abstract
Aggressive types of non-Hodgkin’s lymphoma (NHL) include Burkitt’s lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL), which are germinal center (GC) B-derived lymphomas. The death receptor Fas is expressed in GC B-lymphocytes and contributes to the elimination of nonspecific and autoreactive B cells. Fas has been implicated in lymphomagenesis on the basis of its pro-apoptotic function and in autoimmune lymphoproliferative syndrome, with germline mutations in the Fas gene having been found to predispose individuals to the development of lymphoma. However, the possible mechanisms underlying the impairment of Fas-mediated apoptosis induction during human lymphomagenesis have remained unknown. In the present study, we established a mouse model of mature B-cell lymphoma based on transplantation into recipients of ex vivo-induced GC B-like cells derived from Ink4a/Arf-/- mice and transduced with MYC. Overexpression of MYC and deletion or silence of INK4A/ARF (also known as CDKN2A) are frequently found in both BL and DLBCL. The downregulation of Fas was necessary for both lymphomagenesis and lymphoma cell survival in vivo, suggesting that GC-derived lymphomas require persistent Fas downregulation to evade antitumor immunity by Fas ligand (FasL)-expressing cells. CD40 signal activation in lymphoma cells significantly restored the expression of Fas and thereby induced apoptosis following FasL treatment. Similarly, the majority of human BL and DLBCL cell lines exhibited downregulated Fas, and its restoration by CD40 signal activation. While half of the lymphoma cell lines exhibited high sensitivity to Fas-mediated apoptosis, the remaining cell lines exhibited resistance to it. We found that an inhibitor of the apoptotic protein Livin was responsible for the resistance to Fas-mediated apoptosis and that a high expression of Livin is a poor prognostic factor for patients with BL and DLBCL. We further demonstrated that a bromodomain and extra-terminal (BET) protein BRD4 (bromodomain 4) drives the expression of Livin through its direct binding to the proximal region of the Livin gene promoter, suggesting that the expression of Livin is epigenetically regulated in refractory human lymphoma cells to protect them from immune cytotoxity. Accordingly, the combination of CD40-mediated Fas expression with the targeting of Livin or BET inhibitors is a potential immunotherapeutic strategy for treating aggressive B-cell NHLs.
Citation Format: Sugihara Eiji, Norisato Hashimoto, Satoru Osuka, Sayaka Ueno, Takatsune Shimizu, Shogo Okazaki, Taka-aki Sato, Shinichiro Okamoto, Hideyuki Saya. BRD4 regulates the expression of Livin and thereby confers resistance to Fas-mediated immune cytotoxicity in aggressive B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2348.