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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,6,2]]},"abstract":"<jats:p>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-\u03baB 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.<\/jats:p>","DOI":"10.1073\/pnas.2525164123","type":"journal-article","created":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T18:11:09Z","timestamp":1779819069000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Epstein\u2013Barr virus (EBV) infection causes human germinal center B cell\u2013derived lymphomas in the absence of EBNA2 expression"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6430-413X","authenticated-orcid":false,"given":"Chunyan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6109-8126","authenticated-orcid":false,"given":"Jillian A.","family":"Bristol","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0084-1355","authenticated-orcid":false,"given":"Scott E.","family":"Nelson","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3165-7670","authenticated-orcid":false,"given":"Charlotte","family":"Hendrickson","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana C.","family":"Baiu","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariah","family":"Riel","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2736-6542","authenticated-orcid":false,"given":"Mitch","family":"Hayes","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A.","family":"Ranheim","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1852-2192","authenticated-orcid":false,"given":"Jenny E.","family":"Gumperz","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-9708","authenticated-orcid":false,"given":"Eric C.","family":"Johannsen","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]},{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-6526","authenticated-orcid":false,"given":"Shannon C.","family":"Kenney","sequence":"additional","affiliation":[{"name":"Department of Oncology, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]},{"name":"Department of Medicine, School of Medicine and Public Health, University of Wisconsin","place":["Madison"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,5,26]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2022.08.026"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.26579"},{"key":"e_1_3_4_3_2","first-page":"63","article-title":"Plasmablastic lymphoma: Current perspectives","volume":"8","author":"Lopez A.","year":"2018","unstructured":"A. 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