{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T01:50:31Z","timestamp":1787881831274,"version":"build-2784847793"},"reference-count":80,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite advances in the field, chronic graft-versus-host-disease (cGVHD) remains a leading cause of morbidity and mortality following allogenic hematopoietic stem cell transplant. Because treatment options remain limited, we tested efficacy of anticancer, chromatin-modifying enzyme inhibitors in a clinically relevant murine model of cGVHD with bronchiolitis obliterans (BO). We observed that the novel enhancer of zeste homolog 2 (EZH2) inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 each improved pulmonary function; impaired the germinal center (GC) reaction, a prerequisite in cGVHD\/BO pathogenesis; and JQ5 reduced EZH2-mediated H3K27me3 in donor T cells. Using conditional EZH2 knockout donor cells, we demonstrated that EZH2 is obligatory for the initiation of cGVHD\/BO. In a sclerodermatous cGVHD model, JQ5 reduced the severity of cutaneous lesions. To determine how the 2 drugs could lead to the same physiological improvements while targeting unique epigenetic processes, we analyzed the transcriptomes of splenic GCB cells (GCBs) from transplanted mice treated with either drug. Multiple inflammatory and signaling pathways enriched in cGVHD\/BO GCBs were reduced by each drug. GCBs from JQ5- but not JQ1-treated mice were enriched for proproliferative pathways also seen in GCBs from bone marrow-only transplanted mice, likely reflecting their underlying biology in the unperturbed state. In conjunction with in\u00a0vivo data, these insights led us to conclude that epigenetic targeting of the GC is a viable clinical approach for the treatment of cGVHD, and that the EZH2 inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 demonstrated clinical potential for EZH2i and BETi in patients with cGVHD\/BO.<\/jats:p>","DOI":"10.1182\/blood.2021014557","type":"journal-article","created":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T17:03:02Z","timestamp":1646067782000},"page":"2983-2997","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":16,"title":["BET-bromodomain and EZH2 inhibitor\u2013treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes"],"prefix":"10.1182","volume":"139","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6971-3170","authenticated-orcid":false,"given":"Michael C.","family":"Zaiken","sequence":"first","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Flynn","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katelyn G.","family":"Paz","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Y.","family":"Rhee","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6504-3640","authenticated-orcid":false,"given":"Sujeong","family":"Jin","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4270-8560","authenticated-orcid":false,"given":"Fathima A.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asim","family":"Saha","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Govindarajan","family":"Thangavelu","sequence":"additional","affiliation":[{"name":"Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M. 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