TitleSmall-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsPaz, Katelyn, Flynn Ryan, Du Jing, Qi Jun, Luznik Leo, Maillard Ivan, MacDonald Kelli P., Hill Geoffrey R., Serody Jonathan S., Murphy William J., Sage Peter T., Sharpe Arlene H., Miklos David, Cutler Corey S., Koreth John, Antin Joseph H., Soiffer Robert J., Ritz Jerome, Bradner James E., Melnick Ari M., and Blazar Bruce R.
JournalBlood
Volume133
Issue1
Pagination94-99
Date Published2019 01 03
ISSN1528-0020
KeywordsAnimals, B-Lymphocytes, Bronchiolitis Obliterans, Chronic Disease, Germinal Center, Graft vs Host Disease, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-bcl-6, Small Molecule Libraries, T-Lymphocytes, T-Lymphocytes, Helper-Inducer
Abstract

<p>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.</p>

DOI10.1182/blood-2018-03-839993
Alternate JournalBlood
PubMed ID30279226
PubMed Central IDPMC6318432
Grant ListP30 CA093373 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States
P01 AI056299 / AI / NIAID NIH HHS / United States
R01 AI091627 / AI / NIAID NIH HHS / United States
T32 CA009138 / CA / NCI NIH HHS / United States
R01 HL139730 / HL / NHLBI NIH HHS / United States
P01 CA142106 / CA / NCI NIH HHS / United States