TY - JOUR
T1 - Therapeutic Effects of a NEDD8-Activating Enzyme Inhibitor, Pevonedistat, on Sclerodermatous Graft-versus-Host Disease in Mice
AU - Pai, Chien Chun Steven
AU - Khuat, Lam T.
AU - Chen, Mingyi
AU - Murphy, William J.
AU - Abedi, Mehrdad
N1 - Publisher Copyright:
© 2017 The American Society for Blood and Marrow Transplantation
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Graft-versus-tumor effect
KW - Pevonedistat
KW - Sclerodermatous graft-versus-host disease
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U2 - 10.1016/j.bbmt.2016.10.022
DO - 10.1016/j.bbmt.2016.10.022
M3 - Article
C2 - 27815049
AN - SCOPUS:85006493328
SN - 1083-8791
VL - 23
SP - 30
EP - 37
JO - Biology of Blood and Marrow Transplantation
JF - Biology of Blood and Marrow Transplantation
IS - 1
ER -