Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole treatment option for highly malignant hematologic disease; however, the major complication-graft-versus-host disease (GVHD)-still hinders its clinical application. In addition, chronic GVHD remains the major cause of long-term morbidity and mortality after allo-HSCT. Previously we showed that bortezomib, a proteasome inhibitor, can ameliorate the sclerodermatous GVHD response while maintaining graft-versus-tumor (GVT) effects. Here we report that pevonedistat (MLN4924), an inhibitor of the Nedd8-activating enzyme, which functions upstream of the proteasome in the ubiquitin-proteasome pathway, can also show similar protective effects. Recipient mice treated with pevonedistat demonstrated inhibitory effects on sclerodermatous GVHD pathogenesis. The beneficial effect of pevonedistat was observed to be temporally dependent. Whereas treatment given at the time of allo-HSCT administration or before the onset of symptoms worsened the scleroderma response, therapeutic administration starting at 20 days post-transplantation ameliorated the sclerodermatous GVHD. Flow cytometry analysis revealed differential effects on immune subsets, with inhibition of only antigen-presenting cells and not of donor T cells. Finally, pevonedistat preserved GVT effects in a sclerodermatous murine model of B cell lymphoma. Taken together, these data suggest that inhibition of neddylation with pevonedistat can serve as an alternative approach for the treatment of GVHD while maintaining GVT effects in a murine model of sclerodermatous GVHD.
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
Chien-Chun Steven
CS
Pai
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California.
Lam T
LT
Khuat
Department of Pathology, School of Medicine, University of California, Davis, Sacramento, California.
Mingyi
M
Chen
Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, California; Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California. Electronic address: wmjmurphy@ucdavis.edu.
William J
WJ
Murphy
Department of Internal Medicine, School of Medicine, University of California, Davis, Sacramento, California.
Mehrdad
M
Abedi
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D003517:Cyclopentanes / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000473:pathology; D020350:Graft vs Tumor Effect / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D016393:Lymphoma, B-Cell / Q000628:therapy; D051379:Mice; D011743:Pyrimidines / Q000627:therapeutic use*; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000209:etiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000009:adverse effects; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors
D003517:Cyclopentanes; D004791:Enzyme Inhibitors; C583290:Nedd8-activating enzyme E1 protein, mouse; D011743:Pyrimidines; D044764:Ubiquitin-Activating Enzymes; C539933:pevonedistat
Graft-versus-tumor effect; Pevonedistat; Sclerodermatous graft-versus-host disease