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Precision medicine approaches for MDS-\n                    <jats:italic>SF3B1<\/jats:italic>\n                    remain challenging due to both the complexity of the mis-splicing landscape and its evaluation in disease-accurate models. To uncover novel RNA mis-splicing events, isogenic\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>K700E<\/jats:sup>\n                    and\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>WT<\/jats:sup>\n                    iPSC lines from an MDS-\n                    <jats:italic>SF3B1<\/jats:italic>\n                    patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>K700E<\/jats:sup>\n                    -specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (\n                    <jats:italic>UBA1<\/jats:italic>\n                    ), which encodes a key E1 protein at the apex of the ubiquitination cascade.\n                    <jats:italic>UBA1<\/jats:italic>\n                    mis-splicing (\n                    <jats:italic>UBA1<\/jats:italic>\n                    <jats:sup>ms<\/jats:sup>\n                    ) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34\n                    <jats:sup>+<\/jats:sup>\n                    RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous\n                    <jats:italic>UBA1<\/jats:italic>\n                    <jats:sup>ms<\/jats:sup>\n                    in MDS-\n                    <jats:italic>SF3B1<\/jats:italic>\n                    patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-\n                    <jats:italic>SF3B1<\/jats:italic>\n                    primary CD34\n                    <jats:sup>+<\/jats:sup>\n                    cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define\n                    <jats:italic>UBA1<\/jats:italic>\n                    <jats:sup>ms<\/jats:sup>\n                    as a novel therapeutic vulnerability in\n                    <jats:italic>SF3B1<\/jats:italic>\n                    -mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-\n                    <jats:italic>SF3B1<\/jats:italic>\n                    treatments.\n                  <\/jats:p>","DOI":"10.1038\/s41375-025-02740-1","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T06:49:00Z","timestamp":1756190940000},"page":"2801-2811","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5226-0372","authenticated-orcid":false,"given":"Jonas","family":"Thier","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6625-8348","authenticated-orcid":false,"given":"Sophia","family":"Hofmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8412-4585","authenticated-orcid":false,"given":"Katharina M.","family":"Kirchhof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-3829","authenticated-orcid":false,"given":"Gabriele","family":"Todisco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8399-1430","authenticated-orcid":false,"given":"Teresa","family":"Mortera-Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5270-7268","authenticated-orcid":false,"given":"Ingrid","family":"Lilienthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8690-2010","authenticated-orcid":false,"given":"Dimitris C.","family":"Kanellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1171-2932","authenticated-orcid":false,"given":"Indira","family":"Barbosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3745-503X","authenticated-orcid":false,"given":"Ann-Charlotte","family":"Bj\u00f6rklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2854-5681","authenticated-orcid":false,"given":"Andr\u00e9 G.","family":"Deslauriers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2013-7525","authenticated-orcid":false,"given":"Jiri","family":"Bartek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9468-4543","authenticated-orcid":false,"given":"Nikolas","family":"Herold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1709-8983","authenticated-orcid":false,"given":"Elli","family":"Papaemmanuil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7002-417X","authenticated-orcid":false,"given":"Eirini P.","family":"Papapetrou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7839-3743","authenticated-orcid":false,"given":"Eva","family":"Hellstr\u00f6m-Lindberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0493-5394","authenticated-orcid":false,"given":"Pedro L.","family":"Moura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2335-3370","authenticated-orcid":false,"given":"Vanessa","family":"Lundin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,26]]},"reference":[{"key":"2740_CR1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1111\/j.1365-2141.1982.tb08475.x","volume":"51","author":"JM Bennett","year":"1982","unstructured":"Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, et al. 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