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With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of the KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, it was created using clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in the PSMB5 site and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome inhibitor resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.<\/jats:p>","DOI":"10.1038\/s41598-022-17239-3","type":"journal-article","created":{"date-parts":[[2022,7,30]],"date-time":"2022-07-30T08:48:43Z","timestamp":1659170923000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["A clinically relevant pulse treatment generates a bortezomib-resistant myeloma cell line that lacks proteasome mutations and is sensitive to Bcl-2 inhibitor venetoclax"],"prefix":"10.1038","volume":"12","author":[{"given":"Sondra L.","family":"Downey-Kopyscinski","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sriraja","family":"Srinivasa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexei F.","family":"Kisselev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,7,27]]},"reference":[{"key":"17239_CR1","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1189\/jlb.1011497","volume":"92","author":"S Cenci","year":"2012","unstructured":"Cenci, S. et al. Pivotal Advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors. J. Leukoc. Biol. 92, 921\u2013931. https:\/\/doi.org\/10.1189\/jlb.1011497 (2012).","journal-title":"J. Leukoc. Biol."},{"key":"17239_CR2","first-page":"1","volume":"23","author":"S Cenci","year":"2010","unstructured":"Cenci, S., van Anken, E. & Sitia, R. Proteostenosis and plasma cell pathophysiology. Curr. Opin. Cell Biol. 23, 1\u20137 (2010).","journal-title":"Curr. Opin. Cell Biol."},{"key":"17239_CR3","doi-asserted-by":"publisher","first-page":"3040","DOI":"10.1182\/blood-2008-08-172734","volume":"113","author":"G Bianchi","year":"2009","unstructured":"Bianchi, G. et al. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. 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Proteasome inhibition in multiple myeloma: Head-to-head comparison of currently available proteasome inhibitors. Cell Chem. Biol. 26, 340-351 e343. https:\/\/doi.org\/10.1016\/j.chembiol.2018.11.007 (2019).","journal-title":"Cell Chem. Biol."},{"key":"17239_CR7","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1038\/leu.2009.173","volume":"23","author":"JJ Shah","year":"2009","unstructured":"Shah, J. J. & Orlowski, R. Z. Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 23, 1964\u20131979 (2009).","journal-title":"Leukemia"},{"key":"17239_CR8","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1056\/NEJMoa1411321","volume":"372","author":"AK Stewart","year":"2015","unstructured":"Stewart, A. K. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 372, 142\u2013152. https:\/\/doi.org\/10.1056\/NEJMoa1411321 (2015).","journal-title":"N. Engl. J. 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Other authors do not report any conflicts.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"12788"}}