Therapeutic effects of a NEDD8-activating enzyme inhibitor, pevonedistat, on sclerodermatous graft-versus-host disease in mice
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.
Animals, Antigen-Presenting Cells/drug effects, Cyclopentanes/therapeutic use, Enzyme Inhibitors/therapeutic use, Graft vs Host Disease/drug therapy, Graft vs Tumor Effect/immunology, Hematopoietic Stem Cell Transplantation/adverse effects, Lymphoma, B-Cell/therapy, Mice, Pyrimidines/therapeutic use, Scleroderma, Systemic/drug therapy, T-Lymphocytes/drug effects, Time Factors, Transplantation, Homologous/adverse effects, Ubiquitin-Activating Enzymes/antagonists & inhibitors
30-37
Pai, Chien-Chun Steven
71e42ed8-c823-4543-8ae7-8aed95ee5ab5
Khuat, Lam T
ca00b1c8-4f0e-4f61-bb1a-493f120cef8e
Chen, Mingyi
7c4cf921-859d-4a38-8b24-5f030ee4ca38
Murphy, William J
290fec7b-1d9f-4d5d-80f3-4154fda8970c
Abedi, Mehrdad
ae80515e-d01d-4bb5-9679-8477f14055d8
1 January 2017
Pai, Chien-Chun Steven
71e42ed8-c823-4543-8ae7-8aed95ee5ab5
Khuat, Lam T
ca00b1c8-4f0e-4f61-bb1a-493f120cef8e
Chen, Mingyi
7c4cf921-859d-4a38-8b24-5f030ee4ca38
Murphy, William J
290fec7b-1d9f-4d5d-80f3-4154fda8970c
Abedi, Mehrdad
ae80515e-d01d-4bb5-9679-8477f14055d8
Pai, Chien-Chun Steven, Khuat, Lam T, Chen, Mingyi, Murphy, William J and Abedi, Mehrdad
(2017)
Therapeutic effects of a NEDD8-activating enzyme inhibitor, pevonedistat, on sclerodermatous graft-versus-host disease in mice.
Biology of Blood and Marrow Transplantation, 23 (1), .
(doi:10.1016/j.bbmt.2016.10.022).
Abstract
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.
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Published date: 1 January 2017
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Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Keywords:
Animals, Antigen-Presenting Cells/drug effects, Cyclopentanes/therapeutic use, Enzyme Inhibitors/therapeutic use, Graft vs Host Disease/drug therapy, Graft vs Tumor Effect/immunology, Hematopoietic Stem Cell Transplantation/adverse effects, Lymphoma, B-Cell/therapy, Mice, Pyrimidines/therapeutic use, Scleroderma, Systemic/drug therapy, T-Lymphocytes/drug effects, Time Factors, Transplantation, Homologous/adverse effects, Ubiquitin-Activating Enzymes/antagonists & inhibitors
Identifiers
Local EPrints ID: 495435
URI: http://eprints.soton.ac.uk/id/eprint/495435
ISSN: 1083-8791
PURE UUID: c90f22bd-72cb-4c53-b688-22ffaee21182
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Date deposited: 13 Nov 2024 17:45
Last modified: 19 Dec 2024 03:09
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Author:
Chien-Chun Steven Pai
Author:
Lam T Khuat
Author:
Mingyi Chen
Author:
William J Murphy
Author:
Mehrdad Abedi
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