Regulation of stress tolerance by CREB1 sustains multiple myeloma cell survival

Abstract Multiple myeloma (MM) cells originate from antibody-producing plasma cells and endure chronic oxidative and proteotoxic stress due to the excessive production of immunoglobulins and free light chains. We previously demonstrated that CD56 (also known as neuronal cell adhesion molecule 1) promotes cAMP-responsive element binding (CREB1) activation in MM cells to drive survival, without fully elucidating its mechanism of action. In this study, we describe the global role of CREB1 in regulating tolerance to cellular stresses in MM. Here, we present data to demonstrate that CREB1 directly or indirectly influences key proteins involved in the clearance of oxidants, the unfolded protein response (UPR), and autophagy. In silico data from real patients with MM showed that patients with high CREB1 expression have greater activation of gene sets associated with endurance of stress. We confirmed by genomic and pharmacological modulation that CREB1 activates the mTOR pathway, halting autophagy, and directly binds to the promoter of NRF2 and PERK, modulating genes involved in oxidation and protein stress adaptation. Of particular importance was the identification of TXNIP among the regulated genes. Notably, the TXNIP gene belongs to the 1q21 cytoband, which is amplified in 30 percent of patients with MM, leading to poor outcomes. We showed for the first time that TXNIP inhibition is also toxic against MM cells, interfering with UPR and autophagy. Thus, our data highlights the essential roles of CREB1 and TXNIP in MM cell survival under chronic stress, providing new insights into MM pathophysiology and novel therapeutic strategies for patients with high-risk disease.