title: Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB:p50 NFκB pathway.
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.
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: P
authors.initials: P
authors.lastname: Roy
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: T
authors.initials: T
authors.lastname: Mukherjee
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: B
authors.initials: B
authors.lastname: Chatterjee
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: B
authors.initials: B
authors.lastname: Vijayaragavan
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: B
authors.initials: B
authors.lastname: Banoth
authors.affiliation: Systems Immunology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: S
authors.initials: S
authors.lastname: Basak
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha