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LMP1 contributes to both epithelial and B-cell transformation. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism. To gain insights into key B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells with conditional LMP1 expression. This approach highlighted that LMP highly induces\n                    <jats:italic>de novo<\/jats:italic>\n                    purine biosynthesis, with xanthosine-5-P (XMP) as one of the most highly LMP1-upregulated metabolites. Consequently, IMPDH inhibition by mycophenolic acid (MPA) triggered death of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), a key model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest of Burkitt lymphoma cells with the EBV latency I program, conditional LMP1 expression triggered their death, and this phenotype was rescuable by guanosine triphosphate (GTP) supplementation, implicating LMP1 as a key driver of B-cell GTP biosynthesis. Although both IMPDH isozymes are expressed in LCLs, only IMPDH2 was critical for LCL survival, whereas both contributed to proliferation of Burkitt cells with the EBV latency I program. Both LMP1 C-terminal cytoplasmic tail domains critical for primary human B-cell transformation were important for XMP production, and each contributed to LMP1-driven Burkitt cell sensitivity to MPA. Metabolomic analyses further highlighted roles of NF-kB, mitogen activated kinase, and protein kinase C downstream of LMP1 in support of XMP abundance. Of these, only protein kinase C activity was important for supporting GTP levels in LMP1 expressing Burkitt cells. MPA also de-repressed EBV lytic antigens, including LMP1 itself in latency I Burkitt cells, highlighting crosstalk between the purine biosynthesis pathway and the EBV epigenome. These results suggest novel oncometabolism-based therapeutic approaches to LMP1-driven lymphomas.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013092","type":"journal-article","created":{"date-parts":[[2025,5,14]],"date-time":"2025-05-14T14:20:06Z","timestamp":1747232406000},"page":"e1013092","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Epstein-Barr virus latent membrane protein 1 subverts IMPDH pathways to drive B-cell oncometabolism"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2432-2288","authenticated-orcid":true,"given":"Eric M.","family":"Burton","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Maestri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaowen","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Hua","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bidisha","family":"Mitra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Asara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3965-3418","authenticated-orcid":true,"given":"Benjamin E.","family":"Gewurz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,5,14]]},"reference":[{"issue":"24","key":"ppat.1013092.ref001","doi-asserted-by":"crossref","first-page":"7631","DOI":"10.1111\/febs.16206","article-title":"Cancers associated with human gammaherpesviruses","volume":"289","author":"KW Wen","year":"2022","journal-title":"FEBS J"},{"issue":"11","key":"ppat.1013092.ref002","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1038\/s41579-019-0249-7","article-title":"Latency and lytic replication in Epstein-Barr virus-associated oncogenesis","volume":"17","author":"C M\u00fcnz","year":"2019","journal-title":"Nat Rev Microbiol"},{"key":"ppat.1013092.ref003","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/978-981-10-5765-6_5","article-title":"Current Progress in EBV-Associated B-Cell Lymphomas","volume":"1018","author":"Y 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