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EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-\u03baB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (\u0394EBNA2 EBV) to create the first <jats:italic>in vivo<\/jats:italic> model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both \u0394EBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L\/IL21 expressing feeder layer <jats:italic>in vitro<\/jats:italic> and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1\/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-\u03baB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012132","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T17:26:43Z","timestamp":1713202003000},"page":"e1012132","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice"],"prefix":"10.1371","volume":"20","author":[{"given":"Jillian A.","family":"Bristol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott E.","family":"Nelson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Casco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Hayes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik A.","family":"Ranheim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail S.","family":"Pawelski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deo R.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel J.","family":"Hodson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric C.","family":"Johannsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9655-6526","authenticated-orcid":true,"given":"Shannon C.","family":"Kenney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"ppat.1012132.ref001","doi-asserted-by":"crossref","first-page":"3652","DOI":"10.1016\/j.cell.2022.08.026","article-title":"Epstein-Barr virus: Biology and clinical disease","volume":"185","author":"B Damania","year":"2022","journal-title":"Cell"},{"key":"ppat.1012132.ref002","first-page":"151","article-title":"EBV Persistence\u2014Introducing the Virus","volume":"390","author":"DA Thorley-Lawson","year":"2015","journal-title":"Curr Top Microbiol 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