Epstein–Barr virus (EBV) infection causes human germinal center B cell–derived lymphomas in the absence of EBNA2 expression
Menée à l'aide de modèles murins et de lymphocytes B humains dérivés de centres germinatifs (LBCG), cette étude démontre que l'infection de LBCG normaux par un virus d'Epstein-Barr n'exprimant pas la protéine EBNA2 induit le développement d'un lymphome
The EBV EBNA2 protein is required for EBV-induced transformation of B cells in vitro and drives transcription of the viral promoters used in type III latency. However, most EBV+ lymphomas in immunocompetent humans do not express EBNA2 (likely because type III latency is highly immunogenic) and some human EBV+ BLs contain naturally occurring EBNA2-deleted EBV variants. Here, we show that infection of normal human GC B cells with an EBNA2-deleted EBV mutant results in EBV-induced lymphomas in mice in the absence of EBNA2 expression, inducing tumors that resemble lymphoma types for which in vivo models have been lacking. EBV is associated with 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. Human EBV+ lymphomas that lack EBNA2 expression are largely driven by the viral LMP1 and LMP2A proteins, which activate NF-κB and B cell receptor-like signaling, respectively, or by Myc translocations. However, EBNA2 is required for EBV-mediated transformation of B cells in vitro and there is currently no model system for studying how EBV transforms human GC-derived B cells into lymphomas in vivo in the absence of EBNA2 expression or Myc translocation. Here, we show that human tonsil GC B cells (GCBs) infected with an EBNA2-deleted EBV mutant proliferate on a CD40L/IL21-expressing feeder layer and form lymphomas in NSG mice that resemble human DLBCLs (both ABC and GCB subtypes) and PLs. These EBV-induced lymphomas occur in the absence of Myc overexpression, often have normal karyotypes, and do not contain mutations in cellular genes (including p53) commonly mutated in uninfected human DLBCLs. Using this model system, we show that LMP2A induces plasmablast differentiation, 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.
Proceedings of the National Academy of Sciences , article en libre accès, 2026