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      BET bromodomain inhibition suppresses graft-versus-host disease after allogeneic bone marrow transplantation in mice.

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          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.

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          Author and article information

          Journal
          Blood
          Blood
          American Society of Hematology
          1528-0020
          0006-4971
          Apr 23 2015
          : 125
          : 17
          Affiliations
          [1 ] Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI;
          [2 ] 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;
          [3 ] Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL; and.
          [4 ] 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.
          [5 ] Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China;
          Article
          blood-2014-08-598037
          10.1182/blood-2014-08-598037
          4408296
          25778533
          2d8323d8-0650-4358-ae0a-a5c7b5a289cb
          History

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