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.
Highlights
Multiple myeloma, an incurable plasma cell malignancy, accounts for ~ 13% of all hematological cancers.[1]
Given prevalence of mutations in the non-canonical nuclear factor-κB (NFκB) module in multiple myeloma, we examined if these mutations alter resistance of cancerous cells to apoptotic TNF-related apoptosis-inducing ligand (TRAIL)
It has been suggested that tumor necrosis factor (TNF) instill a refractory state in myeloma cells present in the bone marrow that become resistant to TRAIL
Summary
An incurable plasma cell malignancy, accounts for ~ 13% of all hematological cancers.[1] Disease progression involves clonal expansion of transformed plasma cells into tumors in the bone marrow. Tumor necrosis factor (TNF) induces expression of the pro-survival factors, which are known to confer resistance to apoptotic insults, including TRAIL.[7,8,9] Bone marrow stromal cells provide paracrine TNF signals in myeloma.[10] Serum level of TNF was correlated with disease severity in multiple myeloma,[11,12] and provided for a predictive indicator of high symptom burden for patients undergoing maintenance therapy.[13]
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