Nuclear Respiratory Factor 1 (NRF1) promotes cell survival in Multiple Myeloma under proteasome inhibition therapy

Multiple myeloma (MM) is a complex hematological malignancy characterized by the clonal expansion of plasma cells in the bone marrow, typically preceded by premalignant stages such as MGUS. Despite advances in treatment, MM remains incurable, with resistance to proteasome inhibitors such as bortezomib (BTZ) representing a major clinical challenge. Understanding the interplay between transcription factor activity and epigenetic alterations is therefore crucial to unravel the multilayered pathogenesis of MM. In this study, nuclear respiratory factor 1 (NRF1) is identified as a pivotal transcription factor supporting MM cell survival and contributing to disease progression and drug resistance. Chromatin accessibility profiling (ATAC-seq) of 55 MM samples, integrated with computational footprinting, revealed that NRF1 binding is markedly increased in MM compared with MGUS and correlates with poorer overall survival. Mechanistically, this increase is sustained by a previously uncharacterized enhancer (eNRF1), located 169 kb upstream of the NRF1 promoter and selectively active in malignant plasma cells. Functionally, NRF1 binds to 5,749 MM-specific regulatory regions controlling 103 genes enriched in ubiquitination and unfolded protein response (UPR) pathways. NRF1 depletion disrupted ubiquitin–proteasome homeostasis, triggered ER stress, and reduced proliferation, whereas its overexpression restored survival. NRF1 expression and its downstream program were strongly induced upon BTZ treatment, contributing to acquired resistance. Targeting eNRF1 with antisense oligonucleotides (ASO) decreased NRF1 expression, impaired MM cell growth, and sensitized both sensitive and resistant MM cells to BTZ. In xenograft models, ASO-eNRF1 treatment, alone or combined with BTZ, significantly reduced tumor burden and prolonged survival. Collectively, these findings establish NRF1 as a central regulator of proteasome stress adaptation and identify eNRF1 as a druggable enhancer whose inhibition may overcome drug resistance in MM.