Abstract IA11: Epigenetic mechanisms in pathogenesis and targeted therapy for B-cell lymphomas

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Abstract Recent genome sequencing studies have revealed that somatic mutation of genes that control the epigenome are the most common class of genetic lesion in DLBCLs and FLs. The epigenome is composed of hundreds of distinct chemical modifications of DNA, histones, RNA, and other molecules. Collectively, the epigenome functions as cellular “software”: instructions that encode and determine the phenotype of every type of normal and malignant cell. The fact that mutations in epigenetic modifiers are so common in DLBCL and FL points to the significance of the epigenome in these tumors. The four most common mutations in epigenetic modifiers in DLBCL and FL affect the following genes: KMT2D (also called MLL2), CREBBP, EP300, and EZH2. Eighty percent of lymphoma patients have at least one of these four mutations and often have more than one. Moreover, these mutations usually occur very early during lymphomagenesis and so represent important “founder” events. One fascinating insight that has recently emerged is that these genes play critical roles in germinal center B cells, which are the cells from which DLBCL and FL arise. This is interesting because in many ways germinal center B cells already manifest tumor-like phenotypes. Indeed, it appears that much of the effect of mutations in KMT2D, CREBBP, EP300, and EZH2 is to “lock” B cells into the germinal center mode, which essentially means that it maintains B cells in a highly proliferative, mutagenic state that is hidden from immune surveillance. Fortunately, novel small-molecule inhibitors have been developed that can correct the abnormal epigenomic programs caused by these mutations, and some of these drugs are already showing efficacy in clinical trials. In addition to suppressing lymphoma cells, this kind of treatment may enhance antilymphoma response by restoring immune surveillance. In my talk I will explain how these mechanisms work, and how we can design and implement novel therapeutic regimens that can suppress lymphoma cells with minimal toxicity to other tissues. Citation Format: Ari Melnick. Epigenetic mechanisms in pathogenesis and targeted therapy for B-cell lymphomas [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr IA11.