BET-bromodomain and EZH2 inhibitor-treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes.

Autor:	Zaiken MC; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Flynn R; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Paz KG; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Rhee SY; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Jin S; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Mohamed FA; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Saha A; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Thangavelu G; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Park PMC; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA., Hemming ML; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA., Sage PT; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA.; Evergrande Center for Immunologic Diseases, Harvard Medical School-Brigham and Women's Hospital, Boston, MA., Sharpe AH; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA.; Evergrande Center for Immunologic Diseases, Harvard Medical School-Brigham and Women's Hospital, Boston, MA., DuPage M; Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA., Bluestone JA; University of California San Francisco, San Francisco, CA., Panoskaltsis-Mortari A; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN., Cutler CS; Division of Hematologic Malignancies., Koreth J; Division of Hematologic Malignancies., Antin JH; Division of Hematologic Malignancies., Soiffer RJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Ritz J; Division of Hematologic Malignancies., Luznik L; Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, MD., Maillard I; Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA., Hill GR; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.; Division of Medical Oncology, University of Washington, Seattle, WA., MacDonald KPA; Department of Immunology, Queensland Institute of Medical Research (QIMR), University of Queensland, Brisbane, QLD, Australia., Munn DH; Georgia Cancer Center, Augusta University, Augusta, GA., Serody JS; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC., Murphy WJ; Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA., Kean LS; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA., Zhang Y; Fels Institute for Cancer Research and Molecular Biology, Department of Microbiology and Immunology, Temple University, Philadelphia, PA., Bradner JE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and., Qi J; Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA.; Department of Medicine, Harvard Medical School, Boston, MA., Blazar BR; Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 May 12; Vol. 139 (19), pp. 2983-2997.
DOI:	10.1182/blood.2021014557
Abstrakt:	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 vivo 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. (© 2022 by The American Society of Hematology.)
Databáze:	MEDLINE
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