{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T04:16:46Z","timestamp":1748405806398,"version":"3.41.0"},"reference-count":27,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["20K16410","20K16410","20K16410"],"award-info":[{"award-number":["20K16410","20K16410","20K16410"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["24ek0109609h0003","24ek0109609h0003","24ek0109609h0003","21ek0109334h0004","18ek0109334h0001","24ek0109609h0003"],"award-info":[{"award-number":["24ek0109609h0003","24ek0109609h0003","24ek0109609h0003","21ek0109334h0004","18ek0109334h0001","24ek0109609h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003478","name":"Ministry of Health, Labour and Welfare","doi-asserted-by":"publisher","award":["24FC1001","24FC1001"],"award-info":[{"award-number":["24FC1001","24FC1001"]}],"id":[{"id":"10.13039\/501100003478","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Systemic chronic active Epstein-Barr virus disease (sCAEBV) is a chemotherapy-resistant, EBV-positive T- or NK-cell lymphoproliferative disorder characterized by persistent systemic inflammation driven by the activation of EBV-infected cells. In this study, we explored BCL2, an anti-apoptotic factor implicated in various hematopoietic malignancies, as a potential therapeutic target for sCAEBV, focusing on the effects of its inhibitor, venetoclax. We confirmed BCL2 expression in EBV-positive T- and NK-cell lines and peripheral blood mononuclear cells (PBMCs) from sCAEBV patients using western blotting. Immunofluorescence staining further revealed BCL2 expression in EBV-infected cells within patient-derived PBMCs. Venetoclax treatment reduced the viability of EBV-positive cell lines and patient-derived PBMCs in a dose-dependent manner and induced apoptosis in these cells. Moreover, venetoclax suppressed the mRNA expression of the inflammatory cytokine IFN-\u03b3 in patient-derived PBMCs. To evaluate the in vivo effects of venetoclax, we utilized sCAEBV xenograft model generated by transplanting patient-derived PBMCs into NOD\/Shi-scid\/IL-2R\u03b3null mice. No engraftment of EBV-infected cells was observed in mice treated with venetoclax, whereas one out of three mice in the untreated group exhibited engraftment of EBV-positive cells and tumor formation. Venetoclax treatment showed an insignificant trend to reducing IFN-\u03b3 levels in peripheral blood in established xenograft models. To our knowledge, this is the first report to suggest that venetoclax exerts not only anti-tumor effects but also potential anti-inflammatory effects in sCAEBV. BCL2 represents a promising therapeutic target to address the two pathological characteristics of sCAEBV: malignancy and inflammation.<\/jats:p>","DOI":"10.1038\/s41598-025-03719-9","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T16:29:35Z","timestamp":1748363375000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of venetoclax, a BCL2 inhibitor, in systemic chronic active Epstein-Barr virus disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Ayaka","family":"Ohashi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miwako","family":"Nishio","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mayumi","family":"Yoshimori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaoru","family":"Koike","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morito","family":"Kurata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hayato","family":"Tamai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-Ichi","family":"Imadome","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Arai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"3719_CR1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3389\/fped.2019.00014","volume":"7","author":"A Arai","year":"2019","unstructured":"Arai, A. Advances in the study of chronic active Epstein-Barr virus infection: clinical features under the 2016 WHO classification and mechanisms of development. Front. Pediatr. 7, 14. https:\/\/doi.org\/10.3389\/fped.2019.00014 (2019).","journal-title":"Front. Pediatr."},{"key":"3719_CR2","doi-asserted-by":"publisher","unstructured":"Yoshimori, M. et al. Interferon-\u03b3 produced by EBV-positive neoplastic NK-cells induces differentiation into macrophages and procoagulant activity of monocytes, which leads to HLH. Cancers (Basel)  13 https:\/\/doi.org\/10.3390\/cancers13205097 (2021).","DOI":"10.3390\/cancers13205097"},{"key":"3719_CR3","doi-asserted-by":"publisher","first-page":"2918","DOI":"10.1182\/bloodadvances.2020001451","volume":"4","author":"I Yonese","year":"2020","unstructured":"Yonese, I. et al. Nationwide survey of systemic chronic active EBV infection in Japan in accordance with the new WHO classification. Blood Adv. 4, 2918\u20132926. https:\/\/doi.org\/10.1182\/bloodadvances.2020001451 (2020).","journal-title":"Blood Adv."},{"key":"3719_CR4","doi-asserted-by":"publisher","first-page":"100053","DOI":"10.1016\/j.bneo.2024.100053","volume":"2","author":"Y Uemura","year":"2024","unstructured":"Uemura, Y. et al. JAK1\/2 inhibitor ruxolitinib for the treatment of systemic chronic active Epstein-Barr virus disease: a phase 2 study. Blood Neoplasia. 2, 100053. https:\/\/doi.org\/10.1016\/j.bneo.2024.100053 (2024).","journal-title":"Blood Neoplasia"},{"key":"3719_CR5","doi-asserted-by":"publisher","first-page":"673","DOI":"10.1182\/blood-2011-10-381921","volume":"119","author":"H Kimura","year":"2012","unstructured":"Kimura, H. et al. EBV-associated T\/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases. Blood 119, 673\u2013686. https:\/\/doi.org\/10.1182\/blood-2011-10-381921 (2012).","journal-title":"Blood"},{"key":"3719_CR6","doi-asserted-by":"publisher","first-page":"780","DOI":"10.1002\/ajh.26544","volume":"97","author":"M Yamamoto","year":"2022","unstructured":"Yamamoto, M. et al. Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan. Am. J. Hematol. 97, 780\u2013790. https:\/\/doi.org\/10.1002\/ajh.26544 (2022).","journal-title":"Am. J. Hematol."},{"key":"3719_CR7","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1182\/blood-2007-07-098681","volume":"111","author":"A Majid","year":"2008","unstructured":"Majid, A. et al. BCL2 expression in chronic lymphocytic leukemia: lack of association with the BCL2 938A\u2009>\u2009C promoter single nucleotide polymorphism. Blood 111, 874\u2013877. https:\/\/doi.org\/10.1182\/blood-2007-07-098681 (2008).","journal-title":"Blood"},{"key":"3719_CR8","doi-asserted-by":"publisher","first-page":"3091","DOI":"10.1182\/blood.V81.11.3091.3091","volume":"81","author":"L Campos","year":"1993","unstructured":"Campos, L. et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81, 3091\u20133096 (1993).","journal-title":"Blood"},{"key":"3719_CR9","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.3324\/haematol.2018.204958","volume":"104","author":"A Uchida","year":"2019","unstructured":"Uchida, A. et al. Targeting BCL2 with venetoclax is a promising therapeutic strategy for double-proteinexpression lymphoma with. Haematologica 104, 1417\u20131421. https:\/\/doi.org\/10.3324\/haematol.2018.204958 (2019).","journal-title":"Haematologica"},{"key":"3719_CR10","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1007\/s10238-025-01638-7","volume":"25","author":"F Xu","year":"2025","unstructured":"Xu, F., Bao, X., Huang, W. & Zhou, K. Venetoclax-based low-intensity chemotherapy in the salvage treatment of relapsed\/refractory T-cell acute lymphoblastic leukemia. Clin. Exp. Med. 25, 104. https:\/\/doi.org\/10.1007\/s10238-025-01638-7 (2025).","journal-title":"Clin. Exp. Med."},{"key":"3719_CR11","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/s41408-021-00443-1","volume":"11","author":"PJ Hampel","year":"2021","unstructured":"Hampel, P. J. et al. Venetoclax treatment of patients with relapsed T-cell prolymphocytic leukemia. Blood Cancer J. 11, 47. https:\/\/doi.org\/10.1038\/s41408-021-00443-1 (2021).","journal-title":"Blood Cancer J."},{"key":"3719_CR12","doi-asserted-by":"publisher","first-page":"826","DOI":"10.1200\/JCO.2016.70.4320","volume":"35","author":"MS Davids","year":"2017","unstructured":"Davids, M. S. et al. Phase I First-in-Human study of venetoclax in patients with relapsed or refractory Non-Hodgkin lymphoma. J. Clin. Oncol. 35, 826\u2013833. https:\/\/doi.org\/10.1200\/JCO.2016.70.4320 (2017).","journal-title":"J. Clin. Oncol."},{"key":"3719_CR13","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1056\/NEJMoa1513257","volume":"374","author":"AW Roberts","year":"2016","unstructured":"Roberts, A. W. et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl. J. Med. 374, 311\u2013322. https:\/\/doi.org\/10.1056\/NEJMoa1513257 (2016).","journal-title":"N Engl. J. Med."},{"key":"3719_CR14","doi-asserted-by":"publisher","first-page":"1805","DOI":"10.1182\/bloodadvances.2020002417","volume":"5","author":"M Yoshimori","year":"2021","unstructured":"Yoshimori, M. et al. Antineoplastic and anti-inflammatory effects of bortezomib on systemic chronic active EBV infection. Blood Adv. 5, 1805\u20131815. https:\/\/doi.org\/10.1182\/bloodadvances.2020002417 (2021).","journal-title":"Blood Adv."},{"key":"3719_CR15","doi-asserted-by":"publisher","first-page":"31077","DOI":"10.18632\/oncotarget.25780","volume":"9","author":"E Onozawa","year":"2018","unstructured":"Onozawa, E. et al. STAT3 is constitutively activated in chronic active Epstein-Barr virus infection and can be a therapeutic target. Oncotarget 9, 31077\u201331089. https:\/\/doi.org\/10.18632\/oncotarget.25780 (2018).","journal-title":"Oncotarget"},{"key":"3719_CR16","doi-asserted-by":"publisher","first-page":"107369","DOI":"10.1016\/j.isci.2023.107369","volume":"26","author":"C Liu","year":"2023","unstructured":"Liu, C. et al. Targeting Bcl-xL is a potential therapeutic strategy for extranodal NK\/T cell lymphoma. iScience 26, 107369. https:\/\/doi.org\/10.1016\/j.isci.2023.107369 (2023).","journal-title":"iScience"},{"key":"3719_CR17","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1046\/j.1365-2141.2003.04359.x","volume":"121","author":"Y Zhang","year":"2003","unstructured":"Zhang, Y. et al. Common cytological and cytogenetic features of Epstein-Barr virus (EBV)-positive natural killer (NK) cells and cell lines derived from patients with nasal T\/NK-cell lymphomas, chronic active EBV infection and Hydroa vacciniforme-like eruptions. Br. J. Haematol. 121, 805\u2013814. https:\/\/doi.org\/10.1046\/j.1365-2141.2003.04359.x (2003).","journal-title":"Br. J. Haematol."},{"key":"3719_CR18","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1182\/blood.v97.3.708","volume":"97","author":"H Nagata","year":"2001","unstructured":"Nagata, H. et al. Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T\/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 97, 708\u2013713. https:\/\/doi.org\/10.1182\/blood.v97.3.708 (2001).","journal-title":"Blood"},{"key":"3719_CR19","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1046\/j.1440-1827.2001.01276.x","volume":"51","author":"H Nagata","year":"2001","unstructured":"Nagata, H. et al. Presence of natural killer-cell clones with variable proliferative capacity in chronic active Epstein-Barr virus infection. Pathol. Int. 51, 778\u2013785. https:\/\/doi.org\/10.1046\/j.1440-1827.2001.01276.x (2001).","journal-title":"Pathol. Int."},{"key":"3719_CR20","doi-asserted-by":"publisher","first-page":"e0174136","DOI":"10.1371\/journal.pone.0174136","volume":"12","author":"H Takada","year":"2017","unstructured":"Takada, H. et al. EBV induces persistent NF-\u03baB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells. PLoS One. 12, e0174136. https:\/\/doi.org\/10.1371\/journal.pone.0174136 (2017).","journal-title":"PLoS One"},{"key":"3719_CR21","doi-asserted-by":"publisher","first-page":"2641","DOI":"10.1038\/sj.onc.1205346","volume":"21","author":"A Arai","year":"2002","unstructured":"Arai, A., Kanda, E. & Miura, O. Rac is activated by erythropoietin or interleukin-3 and is involved in activation of the Erk signaling pathway. Oncogene 21, 2641\u20132651. https:\/\/doi.org\/10.1038\/sj.onc.1205346 (2002).","journal-title":"Oncogene"},{"key":"3719_CR22","doi-asserted-by":"publisher","first-page":"9189","DOI":"10.18632\/oncotarget.3279","volume":"6","author":"A Nogami","year":"2015","unstructured":"Nogami, A. et al. FLT3-ITD confers resistance to the PI3K\/Akt pathway inhibitors by protecting the mTOR\/4EBP1\/Mcl-1 pathway through STAT5 activation in acute myeloid leukemia. Oncotarget 6, 9189\u20139205. https:\/\/doi.org\/10.18632\/oncotarget.3279 (2015).","journal-title":"Oncotarget"},{"key":"3719_CR23","unstructured":"Quintanilla-Martinez, L. et al. EBV-positive T-cell and NK-cell lymphoproliferative diseases of childhood. (2017)."},{"key":"3719_CR24","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1128\/JCM.37.1.132-136.1999","volume":"37","author":"H Kimura","year":"1999","unstructured":"Kimura, H. et al. Quantitative analysis of Epstein-Barr virus load by using a real-time PCR assay. J. Clin. Microbiol. 37, 132\u2013136. https:\/\/doi.org\/10.1128\/JCM.37.1.132-136.1999 (1999).","journal-title":"J. Clin. Microbiol."},{"key":"3719_CR25","doi-asserted-by":"publisher","first-page":"e1002326","DOI":"10.1371\/journal.ppat.1002326","volume":"7","author":"K Imadome","year":"2011","unstructured":"Imadome, K. et al. Novel mouse xenograft models reveal a critical role of CD4\u2009+\u2009T cells in the proliferation of EBV-infected T and NK cells. PLoS Pathog. 7, e1002326. https:\/\/doi.org\/10.1371\/journal.ppat.1002326 (2011).","journal-title":"PLoS Pathog"},{"key":"3719_CR26","doi-asserted-by":"publisher","first-page":"3967","DOI":"10.1158\/1078-0432.CCR-17-3004","volume":"24","author":"LV Pham","year":"2018","unstructured":"Pham, L. V. et al. Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas. Clin. Cancer Res. 24, 3967\u20133980. https:\/\/doi.org\/10.1158\/1078-0432.CCR-17-3004 (2018).","journal-title":"Clin. Cancer Res."},{"key":"3719_CR27","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/nm.3048","volume":"19","author":"AJ Souers","year":"2013","unstructured":"Souers, A. J. et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat. Med. 19, 202\u2013208. https:\/\/doi.org\/10.1038\/nm.3048 (2013).","journal-title":"Nat. Med."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-03719-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-03719-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-03719-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T16:29:37Z","timestamp":1748363377000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-025-03719-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":27,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3719"],"URL":"https:\/\/doi.org\/10.1038\/s41598-025-03719-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,27]]},"assertion":[{"value":"15 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 May 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"18569"}}