Journal Article Ahead of print
PubMed: 40920573 DOI: 10.1182/blood.2025028441
Nuclear respiratory factor 1 promotes cell survival in multiple myeloma under proteasome inhibition therapy.
Blood
Authors: Tiziana Bruno, Maria Chiara Cappelletto, Clelia Cortile, Stefano Di Giovenale, Bruno Amadio, Francesca De Nicola, Italia Falcone, Stefano Giuliani, Belinda Palermo, Valeria Catena, Ludovica Ciuffreda, Fulvia Cerruti, Paolo Cascio, Roberta Merola, Serena Masi, Valentina De Pascale, Ombretta Annibali, Silvia Ferraro, Svitlana Gumenyuk, Francesco Pisani, Francesco Marchesi, Andrea Mengarelli, Maurizio Fanciulli, Giacomo Corleone
Affiliations
- IRCCS Regina Elena National Cancer Institute, Rome, Italy.
- San Gallicano Dermatological Institute IRCCS, Rome, Italy.
- IRCCS Regina Elena National Cancer Institute, Italy.
- University of Turin, Italy.
- University of Turin.
- IRCCS Regina Elena National Cancer Institute, Roma, Italy.
- Fondazione Policlinico Universitario Campus Bio Medico, Italy.
- St. Eugenio Hospital, Rome, Italy.
Abstract
Multiple myeloma (MM) continues to be an incurable malignancy, even with recent therapeutic advancements. While epigenetic dysregulation at cis-regulatory elements is known to drive disease progression, the complete molecular mechanisms underlying these alterations are poorly understood. Using ATAC-seq analysis combined with computational footprinting of CD138+ cells from 55 MM patients, 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 (ASOs) 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 manipulation of its regulatory network.
MeSH
Nuclear Respiratory Factor 1, Cells, Hematology, Cell Survival, Nuclear Respiratory Factors, Neoplasms, Disease Progression, Multiple Myeloma, Proteasome Endopeptidase Complex, Therapeutics, Enhancer Elements, Genetic