Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease

Katelyn Paz, Ryan Flynn, Jing Du, Jun Qi, Leo Luznik, Ivan Maillard, Kelli P. MacDonald, Geoffrey R. Hill, Jonathan S. Serody, William J Murphy, Peter T. Sage, Arlene H. Sharpe, David Miklos, Corey S. Cutler, John Koreth, Joseph H. Antin, Robert J. Soiffer, Jerome Ritz, James E. Bradner, Ari M. MelnickBruce R. Blazar

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents.

Original languageEnglish (US)
Pages (from-to)94-99
Number of pages6
JournalBlood
Volume133
Issue number1
DOIs
StatePublished - Jan 3 2019

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Paz, K., Flynn, R., Du, J., Qi, J., Luznik, L., Maillard, I., MacDonald, K. P., Hill, G. R., Serody, J. S., Murphy, W. J., Sage, P. T., Sharpe, A. H., Miklos, D., Cutler, C. S., Koreth, J., Antin, J. H., Soiffer, R. J., Ritz, J., Bradner, J. E., ... Blazar, B. R. (2019). Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease. Blood, 133(1), 94-99. https://doi.org/10.1182/blood-2018-03-839993