Abstract IA23: The role of EZH2 gain-of-function mutations in lymphoma

Abstract

Abstract Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B-cell requirement for T-cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T-cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunologic niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells. Citation Format: Wendy Béguelin. The role of EZH2 gain-of-function mutations in 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 IA23.