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USP8 represents a vulnerability gene in multiple myeloma (MM), suggesting a functional role in the B- and plasma cell compartment. Here we analyzed mice with stage-specific\n                    <jats:italic>Usp8<\/jats:italic>\n                    deletion during B-cell development and investigated its role in patient-derived MM cells that are sensitive or resistant to the proteasome inhibitor Bortezomib (BTZ) using USP8 depletion and treatment with DUB-IN-2, a reported USP8 inhibitor.\n                    <jats:italic>Usp8<\/jats:italic>\n                    depletion in\n                    <jats:italic>Usp8<\/jats:italic>\n                    <jats:sup>f\/f<\/jats:sup>\n                    C\n                    <jats:italic>d19<\/jats:italic>\n                    -Cre mice affected B-cell survival and development favoring immature, innate-like B cells, and germinal center and plasma cells, while also elevating immune-responses and causing Roquin depletion. Cells expressing catalytically inactive USP8 accumulated proteins modified with mixed ubiquitin\/NEDD8 chains indicative of proteotoxic stress, which we identified as preferred USP8 substrates. In MM cells, USP8 knockdown reduced survival via lysosomal dysfunction. In contrast, DUB-IN-2 induced an enhanced ER stress response to treatment with BTZ questioning DUB-IN-2 function as a USP8 inhibitor, as confirmed by biochemical analysis. Thus, our results highlight the therapeutic potential of targeting USP8 and identify the combination of DUB-IN-2 and BTZ as a novel strategy for treating BTZ-resistant MM.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03086-y","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T08:36:32Z","timestamp":1786437392000},"page":"2441-2454","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["USP8 controls proteostasis pathways in B cells and multiple myeloma"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9950-0691","authenticated-orcid":false,"given":"Almut","family":"Dufner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Thery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Monaco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelena","family":"Lazarevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8245-3008","authenticated-orcid":false,"given":"Oliver","family":"Gorka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1924-9530","authenticated-orcid":false,"given":"Nina","family":"Chevalier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7356-6095","authenticated-orcid":false,"given":"Marta","family":"Campos Alonso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5418-0962","authenticated-orcid":false,"given":"Maximilian","family":"Frosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerbrand J.","family":"van der Heden van Noort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kira","family":"Allmeroth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0349-1955","authenticated-orcid":false,"given":"Marco","family":"Prinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Gro\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huib","family":"Ovaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul P.","family":"Geurink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wolfgang W.","family":"Schamel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin S.","family":"Denzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vigo","family":"Heissmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Jacobs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5947-3529","authenticated-orcid":false,"given":"Mirle","family":"Schemionek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Impens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heiko","family":"Bruns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1587-1944","authenticated-orcid":false,"given":"Klaus-Peter","family":"Knobeloch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"3086_CR1","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1007\/s40268-019-0269-9","volume":"19","author":"P Robak","year":"2019","unstructured":"Robak P, Robak T. 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Myeloma patients who were diagnosed and treated at the Department of Haematology at the University Hospital of Erlangen were included. Bone marrow cells were collected and used from left-over material of myeloma patients upon diagnostic bone marrow aspiration, which was approved by the local ethics committee of the University of Erlangen (219_14B, 19-56D). Animal experiments were performed in concordance with existing ethical guidelines and approved by the RP Freiburg (X -20\/02\u2009A and G-16\/104) and the local authorities of North Rhine-Westphalia, Germany (LAVE AZ: 81-02.04.2021.A276). The authors confirm that informed consent was obtained from all study participants. No identifiable images are included in this study.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}