ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
The Nedd8-activating enzyme inhibitor MLN4924 thwarts microenvironment-driven NF-κB activation and induces apoptosis in chronic lymphocytic leukemia B cells.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 87 papers.
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Who cites it
87 citing papers in PubMed, 129 citations in OpenAlex.
- MLN4924 suppresses kidney renal clear cell carcinoma progression through coordinated inhibition of Cullin1 neddylation and PSMB10-associated NF-κB inflammatory signaling.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2026Article
- [Endogenous neddylation in B cells regulates immune responses in mice].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Article
- CD40/PI3K/FOXO1 axis rewiring drives microenvironment-dependent BIM silencing to sustain lymphoma growth and survival.Leukemia · 2026Article
- HIV proviral transcription and infectivity are enhanced by neddylation.Journal of virology · 2025Article
- Inhibiting neddylation: A new strategy for tumor therapy.Journal of pharmaceutical analysis · 2025Review
- Genomic characteristics and prognostic correlations in Chinese multiple myeloma patients.BMC medical genomics · 2025Article
- Article
- Protein neddylation and its role in health and diseases.Signal transduction and targeted therapy · 2024Review
- Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis.Signal transduction and targeted therapy · 2024Article
- Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways.Biomarker research · 2024Review
- Neddylation of protein, a new strategy of protein post-translational modification for targeted treatment of central nervous system diseases.Frontiers in neuroscience · 2024Review
- Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, sensitizes cancer cells to VSVΔ51 oncolytic virotherapy.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy.Acta pharmaceutica Sinica. B · 2023Review
- [Differential expression of NEDD8 in different pathological types of chronic rhinosinusitis with nasal polyps].Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology head and neck surgery · 2023Article
- Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions.Journal of hematology & oncology · 2023Review
- Pharmacologic targeting of Nedd8-activating enzyme reinvigorates T-cell responses in lymphoid neoplasia.Leukemia · 2023Article
- NEDD8 promotes radioresistance via triggering autophagy formation and serves as a novel prognostic marker in oral squamous cell carcinoma.Cancer cell international · 2023Article
- Pevonedistat, a Nedd8-activating enzyme inhibitor, in combination with ibrutinib in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.Blood cancer journal · 2023Article
- Neddylation Regulation of Immune Responses.Research (Washington, D.C.) · 2023Review
- Targeting cullin neddylation for cancer and fibrotic diseases.Theranostics · 2023Review
27 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundStromal-mediated signaling enhances NF-κB pathway activity in chronic lymphocytic leukemia (CLL) B cells, leading to cell survival and chemoresistance. Ubiquitination of IκBα may partially account for constitutive activation of NF-κB. MLN4924 is an investigational agent that inhibits the Nedd8-activating enzyme, thereby neutralizing Cullin-RING ubiquitin ligases and preventing degradation of their substrates. EXPERIMENTAL
designWe conducted a preclinical assessment of MLN4924 in CLL. Primary CLL cells were cocultured in vitro with CD40L-expressing stroma to mimic the prosurvival conditions present in lymphoid tissue. The effect of MLN4924 on CLL cell apoptosis, NF-κB pathway activity, Bcl-2 family members, and cell cycle was assessed by flow cytometry, Western blotting, PCR, and immunocytochemistry.
resultsCD40L-expressing stroma protected CLL cells from spontaneous apoptosis and induced resistance to multiple drugs, accompanied by NF-κB activation and Bim repression. Treatment with MLN4924 induced CLL cell apoptosis and circumvented stroma-mediated resistance. This was accompanied by accumulation of phospho-IκBα, decreased nuclear translocation of p65 and p52 leading to inhibition of both the canonical and noncanonical NF-κB pathways, and reduced transcription of their target genes, notably chemokines. MLN4924 promoted induction of Bim and Noxa in the CLL cells leading to rebalancing of Bcl-2 family members toward the proapoptotic BH3-only proteins. siRNA-mediated knockdown of Bim or Noxa decreased sensitivity to MLN4924. MLN4924 enhanced the antitumor activity of the inhibitors of B-cell receptor (BCR)-associated kinases.
conclusionsMLN4924 disrupts NF-κB activation and induces Bim expression in CLL cells, thereby preventing stroma-mediated resistance. Our data provide rationale for further evaluation of MLN4924 in CLL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.