{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:14:43Z","timestamp":1788545683339,"version":"build-2803163510"},"reference-count":0,"publisher":"American Society of Hematology","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Epstein-Barr virus (EBV) infects many people and causes T-cell and natural killer (NK)-cell disorders, such as chronic active EBV disease and extranodal NK\/T-cell lymphoma, which are aggressive and lack a common genetic driver. This suggests that virus-associated, non-genetic mechanisms contribute to disease. We studied primary T cells, NK cells, Epstein-Barr virus-positive cell lines derived from these disorders, virus-negative controls, and clinical chronic active EBV disease samples. Using genome-wide and single-cell multiome approaches, we examined three-dimensional chromatin organization, histone modifications, viral-host chromatin proximity, regulatory element activity, and transcription. EBV-positive lines shared a chromatin compartment pattern distinct from primary and virus-negative cancer cells. Regions that changed from inactive to active chromatin states showed increased activating histone marks and higher expression of nearby genes. EBV-interacting regions were enriched in inactive chromatin and inactive-to-active shifting regions, and contained activated promoters and enhancers associated with increased expression of neighboring genes in both T-cell and NK-cell backgrounds. Locus-level analyses identified CACNA2D1 and RGS1 as representative target genes with chromatin activation, and knockdown of each gene impaired cell growth in EBV-positive lines. Single-cell multiome profiling of clinical chronic active EBV disease samples identified EBV read-positive T-cell or NK-cell populations consistent with independently defined infected lineages and validated epigenomic and transcriptional rewiring at EBV-interacting regions. These findings support a model in which EBV contributes to oncogenic transcriptional programs in these diseases by coupling three-dimensional chromatin reorganization and regulatory element activation to physical interactions with the host genome.<\/jats:p>","DOI":"10.1182\/blood.2025032640","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:18:48Z","timestamp":1788369528000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["Epstein-Barr virus-associated chromatin activation and enhancer engagement in T\/NK-cell lymphoproliferative diseases"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3552-2662","authenticated-orcid":false,"given":"Shuntaro","family":"Isogai","sequence":"first","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7748-6078","authenticated-orcid":false,"given":"Atsushi","family":"Okabe","sequence":"additional","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazusuke","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1216-4822","authenticated-orcid":false,"given":"Takuya","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8107-6532","authenticated-orcid":false,"given":"Shintaro","family":"Izumi","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine, Chiba University, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2320-1529","authenticated-orcid":false,"given":"Masaki","family":"Fukuyo","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine,Chiba University, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bahityar","family":"Rahmutulla","sequence":"additional","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natsumi","family":"Yoda","sequence":"additional","affiliation":[{"name":"Chiba University Graduate School of Medicine, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4207-1408","authenticated-orcid":false,"given":"Motoaki","family":"Seki","sequence":"additional","affiliation":[{"name":"Chiba University, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5418-1981","authenticated-orcid":false,"given":"Takayuki","family":"Hoshii","sequence":"additional","affiliation":[{"name":"Kanazawa University, Kanazawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7588-278X","authenticated-orcid":false,"given":"Hironori","family":"Yoshiyama","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Shimane University, Izumo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norio","family":"Shimizu","sequence":"additional","affiliation":[{"name":"6Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-6855","authenticated-orcid":false,"given":"Hiroshi","family":"Yasui","sequence":"additional","affiliation":[{"name":"St. Marianna University\u00a0School of Medicine, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Arai","sequence":"additional","affiliation":[{"name":"St. Marianna University School of Medicine, kawawsaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7254-1928","authenticated-orcid":false,"given":"Emiko","family":"Sakaida","sequence":"additional","affiliation":[{"name":"Chiba University Hospital, Chiba, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Kaneda","sequence":"additional","affiliation":[{"name":"Chiba University Health and Disease Omics Center, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,2]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2025032640\/2586838\/blood.2025032640.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2025032640\/2586838\/blood.2025032640.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:03:03Z","timestamp":1788544983000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2025032640\/570716\/Epstein-Barr-virus-associated-chromatin-activation"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,2]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2025032640","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,2]]},"article-number":"blood.2025032640"}}