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While some cases of active NOTCH1 signaling can be explained by mutations in\n                    <jats:italic>NOTCH1<\/jats:italic>\n                    or its regulators, like\n                    <jats:italic>FBXW7<\/jats:italic>\n                    , alternative mechanisms remain elusive. Here, we identified the deubiquitinase USP28 as regulator of NOTCH1 signaling in CLL. Notably,\n                    <jats:italic>USP28<\/jats:italic>\n                    is located within the frequently deleted chr11q23 region and is deleted in 90% of del(11q) patients, resulting in its decreased expression. USP28 interacts with the NOTCH1 intracellular domain (NICD) independently of FBXW7 and the NICD-PEST domain, stabilizing NICD and enhancing NOTCH1 signaling. Integrating RBPJ-occupied genes in HG3 cells, RNA-Seq of\n                    <jats:italic>USP28<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>WT<\/jats:italic>\n                      \/\n                      <jats:italic>KO<\/jats:italic>\n                    <\/jats:sup>\n                    cells and gene expression from del(11q) CLL patients, we identified 15 NOTCH1 target genes specifically dysregulated by deletion of USP28 and del(11q) potentially influencing CLL pathogenesis. Pharmacological inhibition of USP28 with the small molecule AZ1 suppressed NOTCH1 activation in primary CLL cells. AZ1 combined with the BCL-2 inhibitor venetoclax reduced CLL cell viability, particularly in samples with high NOTCH1 activity. Our findings highlight USP28 as promising therapeutic target and provide a rationale for combined inhibition of USP28 and BCL-2 in CLL patients with active NOTCH1 signaling.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02632-4","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T05:26:55Z","timestamp":1748842015000},"page":"1892-1904","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL"],"prefix":"10.1038","volume":"39","author":[{"given":"Alena Sophie","family":"Ehrmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Quijada-\u00c1lamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Close","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Carracoi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"P\u00e9rez-Carretero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4577-8599","authenticated-orcid":false,"given":"Luis Antonio","family":"Corchete","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Friedrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0384-325X","authenticated-orcid":false,"given":"Benedetto Daniele","family":"Giaimo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5473-4398","authenticated-orcid":false,"given":"Deyan Yordanov","family":"Yosifov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1433-9702","authenticated-orcid":false,"given":"Johannes","family":"Bloehdorn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Rodr\u00edguez-S\u00e1nchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugen","family":"Tausch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christof","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2116-5536","authenticated-orcid":false,"given":"Hartmut","family":"D\u00f6hner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Kietzmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4325-5452","authenticated-orcid":false,"given":"Tilman","family":"Borggrefe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6830-9296","authenticated-orcid":false,"given":"Stephan","family":"Stilgenbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2923-5765","authenticated-orcid":false,"given":"Franz","family":"Oswald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jes\u00fas-Mar\u00eda","family":"Hern\u00e1ndez-Rivas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0227-7188","authenticated-orcid":false,"given":"Daniel","family":"Mertens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"2632_CR1","doi-asserted-by":"publisher","first-page":"1910","DOI":"10.1056\/NEJM200012283432602","volume":"343","author":"H D\u00f6hner","year":"2000","unstructured":"D\u00f6hner H, Stilgenbauer S, Benner A, Leupolt E, Kr\u00f6ber A, Bullinger L, et al. 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