Biology

Dr. Soumen Basak
National Institute of Immunology, Delhi

Environmental drug resistance constitutes a serious impediment for therapeutic intervention in multiple myeloma.  Tumor promoting cytokines, such as TNF, induce NF-κB driven expression of pro-survival factors, which confer resistance in myeloma cells to apoptotic insults from TRAIL and other chemotherapeutic drug.  It is thought that RelA:p50 dimer activated upon TNF-induced canonical NF-κB signaling mediates the pro-survival NF-κB function in cancerous cells.  Myeloma cells additionally acquire gain-of-function mutations in the non-canonical NF-κB module, which is known to control RelB:p52/NF-kB activity during immune cell-differentiation.  However, role of non-canonical NF-kB signaling in the drug resistance in multiple myeloma remains unclear.  Here we report that myeloma-associated non-canonical aberrations reinforce TNF signaling in producing a protracted TRAIL-refractory state.  These mutations did not act through typical p52 NF-κB complex, but depleted p100 to reposition RelB under TNF control.  More so, engagement of an autoregulatory circuit prolonged TNF-induced NF-kB response, albeit composed of an alternate RelB:p50/NF-kB dimer.  Intriguingly, TNF-activated RelB:p50 dimer was both necessary and sufficient, and RelA was not required, for NF-κB dependent gene-expressions and suppression of TRAIL-induced apoptosis in myeloma cells harboring non-canonical mutations.  In sum, we provide evidence that cancer-associated mutations modify TNF-induced NF-κB activity in exacerbating environmental drug-resistance.