title: BET bromodomain inhibition suppresses graft-versus-host disease after allogeneic bone marrow transplantation in mice.
abstract: Acute graft-versus-host disease (GVHD) is the major obstacle of allogeneic bone marrow transplantation (BMT). Bromodomain and extra-terminal (BET) protein inhibitors selectively block acetyl-binding pockets of the bromodomains and modulate histone acetylation. Here, we report that inhibition of BET bromodomain (BRD) proteins with I-BET151 alters cytokine expression in dendritic cells (DCs) and T cells, including surface costimulatory molecules, in vitro and in vivo cytokine secretion, and expansion. Mechanistic studies with I-BET151 and JQ1, another inhibitor, demonstrate that these effects could be from disruption of association between BRD4 and acetyl-310 RelA of nuclear factor kappa B. Short-term administration early during BMT reduced GVHD severity and improved mortality in two different allogeneic BMT models but retained sufficient graft-versus-tumor effect. Thus inhibiting BRD proteins may serve as a novel approach for preventing GVHD.
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Yaping
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China;
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Tomomi
authors.initials: T
authors.lastname: Toubai
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Katherine
authors.initials: K
authors.lastname: Oravecz-Wilson
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL; and.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Nathan
authors.initials: N
authors.lastname: Mathewson
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Graduate Program in Immunology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Julia
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Corinne
authors.initials: C
authors.lastname: Rossi
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Emily
authors.initials: E
authors.lastname: Cummings
authors.affiliation: Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China;
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Shaomeng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D014184:Transplantation, Homologous; D000092468:Bromodomain Containing Proteins
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D016328:NF-kappa B; D009687:Nuclear Proteins; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A