ArticleOncogene2017
Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 45 citations in OpenAlex.
- Clinical benefit of ixazomib plus lenalidomide-dexamethasone in myeloma patients with non-canonical NF-κB pathway activation.European journal of haematology · 2020Trial
- Stage-Specific Reconstruction of Genome-Wide Genetic and Epigenetic Regulatory Networks Reveals Mechanistic Insights into Asthma Progression.International journal of molecular sciences · 2026Article
- The mTORC2 subunit RICTOR drives breast cancer progression by promoting ganglioside biosynthesis through transcriptional and epigenetic mechanisms.PLoS biology · 2025Article
- New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy.Journal of pharmaceutical analysis · 2025Review
- IFI35 regulates non-canonical NF-κB signaling to maintain glioblastoma stem cells and recruit tumor-associated macrophages.Cell death and differentiation · 2024Article
- The Genetic and Molecular Drivers of Multiple Myeloma: Current Insights, Clinical Implications, and the Path Forward.Pharmacogenomics and personalized medicine · 2024Review
- Knockouts ofInternational journal of molecular sciences · 2023Article
- Article
- The NF-κB multidimer system model: A knowledge base to explore diverse biological contexts.Science signaling · 2023Review
- The NFκB signaling system in the generation of B-cell subsets: from germinal center B cells to memory B cells and plasma cells.Frontiers in immunology · 2023Review
- COX2 confers bone marrow stromal cells to promoting TNFα/TNFR1β-mediated myeloma cell growth and adhesion.Cellular oncology (Dordrecht, Netherlands) · 2021Article
- Review
- A Kinase Assay for Measuring the Activity of the NIK-IKK1 Complex Induced via the Noncanonical NF-κB Pathway.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Article
- First Insight into the Modulation of Noncanonical NF-κB Signaling Components by Poxviruses in Established Immune-Derived Cell Lines: An In Vitro Model of Ectromelia Virus Infection.Pathogens (Basel, Switzerland) · 2020Article
- RelB sustains endocrine resistant malignancy: an insight of noncanonical NF-κB pathway into breast Cancer progression.Cell communication and signaling : CCS · 2020Article
- Novel complementary antitumour effects of celastrol and metformin by targeting IκBκB, apoptosis and NLRP3 inflammasome activation in diethylnitrosamine-induced murine hepatocarcinogenesis.Cancer chemotherapy and pharmacology · 2020Article
- A mechanism for epithelial-mesenchymal heterogeneity in a population of cancer cells.PLoS computational biology · 2020Article
- Role of NF-kappaB2-p100 in regulatory T cell homeostasis and activation.Scientific reports · 2019Article
- Chandipura Virus Utilizes the Prosurvival Function of RelA NF-κB for Its Propagation.Journal of virology · 2019Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumor-promoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-κB (NFκB)- driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TNF-related apoptosis-inducing ligand (TRAIL) and other chemotherapeutic drugs. It is thought that RelA:p50 dimer, activated from IκBα-inhibited complex in response to TNF-induced canonical NFκB signal, mediates the pro-survival NFκB function in cancerous cells. Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NFκB module, which induces partial proteolysis of p100 into p52 to promote RelB:p52/NFκB activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NFκB signaling in the drug resistance in multiple myeloma remains unclear. Here we report that myeloma-associated non-canonical aberrations reinforce pro-survival TNF signaling in producing a protracted TRAIL-refractory state. These mutations did not act through a typical p52 NFκB complex, but completely degraded p100 to reposition RelB under IκBα control, whose degradation during TNF signaling induced an early RelB:p50 containing NFκB activity. More so, autoregulatory RelB synthesis prolonged this TNF-induced RelB:p50 activity in myeloma cells harboring non-canonical mutations. Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NFκB-dependent pro-survival gene expressions and suppression of apoptosis. Indeed, high RelB mRNA expressions in myeloma patients correlated with the augmented level of pro-survival factors and resistance to therapeutic intervention. In sum, we provide evidence that cancer-associated mutations perpetuate TNF-induced pro-survival NFκB activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.
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