Non-canonical NFκB mutations reinforce pro-survival TNF response in multiple myeloma through an autoregulatory RelB: p50 NFκB pathway

Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma. Tumorpromoting cytokines, such as tumor necrosis factor (TNF), induce nuclear factor-kappa B (NF kappa B)-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 I.Ba-inhibited complex in response to TNF-induced canonical NF kappa B signal, mediates the pro-survival NF kappa B function in cancerous cells. Myeloma cells additionally acquire gain-offunction mutations in the non-canonical N kappa B module, which induces partial proteolysis of p100 into p52 to promote RelB: p52/NF kappa B activation from p100-inhibited complex during immune cell differentiation. However, role of non-canonical NF kappa B 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 NF kappa B complex, but completely degraded p100 to reposition RelB under I kappa Ba control, whose degradation during TNF signaling induced an early RelB: p50 containing NF kappa B 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 NF kappa B-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 NF kappa B activity through autoregulatory RelB control and thereby exacerbate environmental drug resistance in multiple myeloma.