{"entity": "researcher", "timestamp": "2026-08-20T20:53:44.385Z", "family": "Barbosa", "given": "Indira", "initials": "I", "orcid": "0009-0004-1171-2932", "affiliations": ["Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/2c92d74875a9433fafc001f47e3f48c3.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/2c92d74875a9433fafc001f47e3f48c3"}}, "publications": [{"entity": "publication", "iuid": "4fa302a131c347a4967d5d96e978a559", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/4fa302a131c347a4967d5d96e978a559.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/4fa302a131c347a4967d5d96e978a559"}}, "title": "SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.", "authors": [{"family": "Thier", "given": "Jonas", "initials": "J", "orcid": "0009-0007-5226-0372", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2670901806e94464820ea6749c625a41.json"}}, {"family": "Hofmann", "given": "Sophia", "initials": "S", "orcid": "0009-0006-6625-8348", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5299df88b9d04e93b39f5a2ec32f4e26.json"}}, {"family": "Kirchhof", "given": "Katharina M", "initials": "KM", "orcid": "0000-0001-8412-4585", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6fd0174077664b6c94b948c4b6f97346.json"}}, {"family": "Todisco", "given": "Gabriele", "initials": "G", "orcid": "0000-0001-6583-3829", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/769f70d382bc46cfbfffa0b5cd16710f.json"}}, {"family": "Mortera-Blanco", "given": "Teresa", "initials": "T", "orcid": "0000-0002-8399-1430", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2afa2c9bceb44bd7aa4810e7846b5607.json"}}, {"family": "Lilienthal", "given": "Ingrid", "initials": "I", "orcid": "0000-0001-5270-7268", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/5831c58c547d47f9826997c52763a30b.json"}}, {"family": "Kanellis", "given": "Dimitris C", "initials": "DC", "orcid": "0000-0001-8690-2010", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/14307e4299ce40a49d2e45265398676c.json"}}, {"family": "Barbosa", "given": "Indira", "initials": "I", "orcid": "0009-0004-1171-2932", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2c92d74875a9433fafc001f47e3f48c3.json"}}, {"family": "Bj\u00f6rklund", "given": "Ann-Charlotte", "initials": "AC", "orcid": "0009-0008-3745-503X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2646432d278e40b79a75cbb5222ceb39.json"}}, {"family": "Deslauriers", "given": "Andr\u00e9 G", "initials": "AG", "orcid": "0000-0002-2854-5681", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/2bcb1a0e3ce6438ab3aec7e24a383d3a.json"}}, {"family": "Bartek", "given": "Jiri", "initials": "J", "orcid": "0000-0003-2013-7525", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/288939950c0c4c6393d35c84e5128b5f.json"}}, {"family": "Herold", "given": "Nikolas", "initials": "N", "orcid": "0000-0001-9468-4543", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/749eedaa5f69414aa315bb875eef9475.json"}}, {"family": "Papaemmanuil", "given": "Elli", "initials": "E", "orcid": "0000-0003-1709-8983", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/6ea61c4aa9324a398fffe747c0e7824d.json"}}, {"family": "Papapetrou", "given": "Eirini P", "initials": "EP", "orcid": "0000-0001-7002-417X", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/7951631751334226bc25259c6af73da8.json"}}, {"family": "Hellstr\u00f6m-Lindberg", "given": "Eva", "initials": "E", "orcid": "0000-0002-7839-3743", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/66eecd3e3886496cb7f7dcaefa5e6a36.json"}}, {"family": "Moura", "given": "Pedro L", "initials": "PL", "orcid": "0000-0002-0493-5394", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/ac418bab887f4153b20d77dfc455b3a7.json"}}, {"family": "Lundin", "given": "Vanessa", "initials": "V", "orcid": "0000-0003-2335-3370", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/9b746851c7044c7f8563cc39ed9f457e.json"}}], "type": "journal article", "published": "2025-11-00", "journal": {"title": "Leukemia", "issn": "1476-5551", "volume": "39", "issue": "11", "pages": "2801-2811", "issn-l": "0887-6924"}, "abstract": "Myelodysplastic syndromes with somatic mutations in the splicing factor SF3B1 gene (MDS-SF3B1) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-SF3B1 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 SF3B1K700E and SF3B1WT iPSC lines from an MDS-SF3B1 patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified SF3B1K700E-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (UBA1), which encodes a key E1 protein at the apex of the ubiquitination cascade. UBA1 mis-splicing (UBA1ms) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34+ RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous UBA1ms in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 primary CD34+ cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define UBA1ms as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.", "doi": "10.1038/s41375-025-02740-1", "pmid": "40858805", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC12589102"}, {"db": "pii", "key": "10.1038/s41375-025-02740-1"}], "notes": [], "created": "2026-08-20T08:47:24.962Z", "modified": "2026-08-20T08:47:51.017Z"}]}