LAUSR

Despite advances in the field, chronic graft-vs-host-disease (cGVHD) remains a leading cause of morbidity and mortality following allogenic hematopoietic stem cell transplant. As treatment options remain limited, we tested efficacy of anti-cancer, 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 two 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 pro-proliferative pathways also seen in GCBs from BM-Only transplanted mice, likely reflecting their underlying biology in the unperturbed state. In conjunction with in vivo data these insights lead 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.