Abstract
Multiple myeloma (MM) continues to be an incurable malignancy, even with recent therapeutic advancements. Although epigenetic dysregulation at cis-regulatory elements is known to drive disease progression, the complete molecular mechanisms underlying these alterations are poorly understood. Using Assay for Transposase-Accessible Chromatin with high-throughput sequencing analysis combined with the computational footprinting of CD138+ cells from 55 patients with MM, we depicted the dynamic changes in chromatin accessibility during disease progression and identified nuclear respiratory factor 1 (NRF1) as a master regulator of vital MM survival pathways. We demonstrated that NRF1 maintains proteasome homeostasis by orchestrating the ubiquitination pathway, which is essential for MM cell survival. We discovered a novel enhancer element that physically interacts with the NRF1 promoter, sustaining its expression. Targeting this enhancer RNA reduced NRF1 levels and increased tumor cell sensitivity to bortezomib (BTZ), suggesting therapeutic potential. In xenograft models, we showed that antisense oligonucleotides targeting the NRF1 enhancer, either alone or combined with BTZ, significantly decreased tumor burden and improved survival. Our findings reveal a previously unknown NRF1-dependent mechanism regulating MM cell survival and present a promising therapeutic approach through the manipulation of its regulatory network.