github link
Accession IconGSE138560

Expression profiling of CLL derived T Cells treated with pevonedistat

Organism Icon Homo sapiens
Sample Icon 16 Downloadable Samples
Technology Badge Icon Affymetrix Clariom S Human array (clariomshuman)

Submitter Supplied Information

Description
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 while targeting NAE results in markedly differential expression of NF-κB-regulated genes and downregulation of IL-2 signaling during T-cell activation, T cells evade apoptosis. Meanwhile, NAE inhibition favorably modulates polarization of T cells in vitro, with decreased Treg differentiation and a shift towards TH1 phenotype, accompanied by increased interferon-γ production. These findings were recapitulated in vivo in immunocompetent mouse models. T cells exposed to pevonedistat in washout experiments, informed by its human pharmacokinetic profile, recover NAE activity and maintain their response to T-cell receptor stimulation and cytotoxic potential. Our data shed light on the potential immune implications of targeting neddylation in CLL and lymphoid malignancies.
PubMed ID
No associated PubMed ID
Publication Title
No associated publication
Total Samples
16
Submitter’s Institution
Authors
No associated authors

Samples

Show of 0 Total Samples
Filter
Add/Remove
Accession Code
Title
Specimen part
Disease
Disease stage
Subject
Time
Processing Information
Additional Metadata
No rows found
Loading...