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

Michael C. Zaiken, Ryan Flynn, Katelyn G. Paz, Stephanie Y. Rhee, Sujeong Jin, Fathima A. Mohamed, Asim Saha, Govindarajan Thangavelu, Paul M.C. Park, Matthew L. Hemming, Peter T. Sage, Arlene H. Sharpe, Michel DuPage, Jeffrey A. Bluestone, Angela Panoskaltsis-Mortari, Corey S. Cutler, John Koreth, Joseph H. Antin, Robert J. Soiffer, Jerome RitzLeo Luznik, Ivan Maillard, Geoffrey R. Hill, Kelli P.A. MacDonald, David H. Munn, Jonathan S. Serody, William J. Murphy, Leslie S. Kean, Yi Zhang, James E. Bradner, Jun Qi, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2983-2997
Number of pages15
JournalBlood
Volume139
Issue number19
DOIs
StatePublished - May 12 2022

Bibliographical note

Funding Information:
This work was supported, in part, by National Institutes of Health, National Cancer Institute (P01 CA142106), National Institute of Allergy and Infectious Disease (P01 AI56299, T32 AI007313, and R01 CA222218), Leukemia Society of America Translational Research Grant 6458-15, and the Children's' Cancer Research Fund.

Funding Information:
Conflict-of-interest disclosure: B.R.B. receives remuneration as an advisor to Magenta Therapeutics and BlueRock Therapeutics; research funding from BlueRock Therapeutics, Rheos Medicines, Equilibre biopharmaceuticals, and Carisma Therapeutics, Inc.; and is a cofounder of Tmunity Therapeutics. J.Q. is a scientific cofounder and consultant for Epiphanes and a consultant for Talus. G.R.H. has consulted for Generon Corporation, NapaJen Pharma, iTeos Therapeutics, and Neoleukin Therapeutics and has received research funding from Compass Therapeutics, Syndax Pharmaceuticals, Applied Molecular Transport, Serplus Technology, Heat Biologics, Laevoroc Oncology, and iTeos Therapeutics. The remaining authors declare no competing financial interests.

Publisher Copyright:
© 2022 American Society of Hematology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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