EBV-Associated Lymphoma Consortium Annual Meeting (Abstract): Submission #3

Abstract Summary EBV causes human B-cell lymphomas, including Burkitt lymphomas (BLs), diffuse large B cell lymphomas (DLBCLs), Hodgkin lymphomas (HLs) and Plasmablastic lymphomas (PLs). EBV+ lymphomas in immunocompetent humans are usually derived from germinal center (GC)-experienced B cells and have stringent latency forms that do not express the viral transforming protein, EBNA2. EBV+ lymphomas with “Type II” latency (the most common latency type in DLBCLs and HLs) are driven by the LMP1 and LMP2A EBV proteins, which activate NF-KB and B-cell receptor-like signaling, respectively. However, there is currently no model system for studying how type II latency transforms normal human GC-derived B cells into lymphomas in vivo. Here we show that tonsil GC B cells (GCBs) infected with an EBNA2-deleted EBV mutant (ΔEBNA2) proliferate indefinitely on a CD40L/IL21-expressing feeder layer and form lymphomas in NSG mice that resemble human DLBCLs and PLs. ΔEBNA2-infected tumors that have high-level LMP2A expression (with type II latency) form lymphomas that express plasmablast markers, while tumors with LMP2A-negative “Wp-restricted” latency (a latency type found in some EBV+ human BLs) have a GCB DLBCL-like phenotype. Using this novel model system, we show that LMP2A activates expression of cellular proteins required for plasmablast differentiation and decreases expression of cellular proteins required for GCB and B-cell identity. Furthermore, LMP2A increases expression of genes involved in lymphocyte mobility and trafficking and enhances tumor invasiveness in vivo. This new model system can thus be used to define roles of viral and cellular proteins in EBV-induced human GCB-derived lymphomas that lack EBNA2 expression