Multiple myeloma cells depend on the DDI2/NRF1-mediated proteasome stress response for survival

• Main Authors: Anderson, K.C (Author), Bianchi, G. (Author), Briere, J. (Author), Chen, T. (Author), Czarnecki, P.G (Author), Ho, M. (Author), Keith Blackwell, T. (Author), Moscvin, M. (Author)
• Format: Article
• Language: English
• Published: American Society of Hematology 2022
• Subjects: animal cell; animal experiment; animal model; animal tissue; Article; aspartic proteinase; biogenesis; bortezomib; cancer resistance; carfilzomib; catalysis; cell nucleus; cell survival; cellular stress response; chemosensitivity; controlled study; disease exacerbation; DNA damage inducible 1 homolog 2 protein; drug cytotoxicity; enzyme activation; enzyme activity; enzyme defect; enzyme deficiency; enzyme inhibition; enzyme synthesis; female; human; human cell; in vitro study; in vivo study; interocular transfer; molecularly targeted therapy; mouse; multiple myeloma; myeloma cell; nelfinavir; nonhuman; proteasome; proteasome inhibitor; protein cleavage; protein function; protein protein interaction; protein structure; protein transport; transcription factor Nrf1; transcription initiation; unclassified drug
• Online Access: View Fulltext in Publisher

 Multiple myeloma (MM) cells suffer from baseline proteotoxicity as the result of an imbalance between the load of misfolded proteins awaiting proteolysis and the capacity of the ubiquitin-proteasome system to degrade them. This intrinsic vulnerability is at the base ofMMsensitivity to agents that perturb proteostasis, such as proteasome inhibitors (PIs), the mainstay of modern-day myeloma therapy. De novo and acquired PI resistance are important clinical limitations that adversely affect prognosis. The molecular mechanisms underpinning PI resistance are only partially understood, limiting the development of drugs that can overcome it. The transcription factor NRF1 is activated by the aspartic protease DNA damage inducible 1 homolog 2 (DDI2) upon proteasome insufficiency and governs proteasome biogenesis. In this article, we show thatMMcells exhibit baseline NRF1 activation and are dependent upon DDI2 for survival. DDI2 knockout (KO) is cytotoxic for MMcells, both in vitro and in vivo. Protein structure-function studies show that DDI2 KO blocks NRF1 cleavage and nuclear translocation, causing impaired proteasome activity recovery upon irreversible proteasome inhibition and, thereby, increasing sensitivity to PIs. Add-back of wild-type, but not of catalytically dead DDI2, fully rescues these phenotypes. We propose that DDI2 is an unexplored promising molecular target inMMby disrupting the proteasome stress response and exacerbating proteotoxicity. © 2022 American Society of Hematology. All rights reserved.