Immunomodulatory effects of pevonedistat, a NEDD8-activating enzyme inhibitor, in chronic lymphocytic leukemia-derived T cells.
Antineoplastic Agents
/ pharmacology
Cell Line, Tumor
Cyclopentanes
/ pharmacology
Enzyme Inhibitors
/ pharmacology
Humans
Immunomodulation
/ drug effects
Leukemia, Prolymphocytic, T-Cell
/ drug therapy
Lymphocyte Activation
/ drug effects
Models, Biological
NEDD8 Protein
/ antagonists & inhibitors
Pyrimidines
/ pharmacology
Receptors, Antigen, T-Cell
/ metabolism
Signal Transduction
T-Lymphocytes
/ drug effects
T-Lymphocytes, Helper-Inducer
/ drug effects
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
09
10
2019
accepted:
03
03
2020
revised:
25
02
2020
pubmed:
24
3
2020
medline:
14
1
2021
entrez:
24
3
2020
Statut:
ppublish
Résumé
Novel targeted agents used in therapy of lymphoid malignancies, such as inhibitors of B-cell receptor-associated kinases, are recognized to have complex immune-mediated effects. NEDD8-activating enzyme (NAE) has been identified as a tractable target in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma. We and others have shown that pevonedistat (TAK-924), a small-molecule inhibitor of NAE, abrogates NF-κB signaling in malignant B cells. However, NF-κB pathway activity is indispensable in immune response, and T-cell function is altered in patients with CLL. Using T cells derived from patients with CLL, we demonstrate that although targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of interleukin (IL)-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased T
Identifiants
pubmed: 32203139
doi: 10.1038/s41375-020-0794-0
pii: 10.1038/s41375-020-0794-0
pmc: PMC8288064
mid: NIHMS1718969
doi:
Substances chimiques
Antineoplastic Agents
0
Cyclopentanes
0
Enzyme Inhibitors
0
NEDD8 Protein
0
NEDD8 protein, human
0
Pyrimidines
0
Receptors, Antigen, T-Cell
0
pevonedistat
S3AZD8D215
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
156-168Subventions
Organisme : NCI NIH HHS
ID : U01 CA217862
Pays : United States
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