Jonas Thier, Sophia Hofmann, Katharina M. Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C. Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G. Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P. Papapetrou, Eva Hellström-Lindberg, Pedro L. Moura, Vanessa Lundin
{"title":"SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms","authors":"Jonas Thier, Sophia Hofmann, Katharina M. Kirchhof, Gabriele Todisco, Teresa Mortera-Blanco, Ingrid Lilienthal, Dimitris C. Kanellis, Indira Barbosa, Ann-Charlotte Björklund, André G. Deslauriers, Jiri Bartek, Nikolas Herold, Elli Papaemmanuil, Eirini P. Papapetrou, Eva Hellström-Lindberg, Pedro L. Moura, Vanessa Lundin","doi":"10.1038/s41375-025-02740-1","DOIUrl":null,"url":null,"abstract":"<p>Myelodysplastic syndromes with somatic mutations in the splicing factor <i>SF3B1</i> gene (MDS-<i>SF3B1</i>) result in RNA mis-splicing, erythroid dysplasia and ultimately refractory anemia. Precision medicine approaches for MDS-<i>SF3B1</i> 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 <i>SF3B1</i><sup>K700E</sup> and <i>SF3B1</i><sup>WT</sup> iPSC lines from an MDS-<i>SF3B1</i> patient were differentiated into hematopoietic cells and analyzed via unsupervised splicing event profiling using full-length RNA sequencing. This identified <i>SF3B1</i><sup>K700E</sup>-specific mis-splicing of ubiquitin-like modifier activating enzyme 1 (<i>UBA1</i>), which encodes a key E1 protein at the apex of the ubiquitination cascade. <i>UBA1</i> mis-splicing (<i>UBA1</i><sup>ms</sup>) introduced protein instability and decreased total UBA1 levels, rendering mutated cells susceptible to the small-molecule UBA1 inhibitor TAK-243. Analysis of CD34<sup>+</sup> RNA sequencing data from an MDS patient cohort confirmed unique and ubiquitous <i>UBA1</i><sup>ms</sup> in MDS-<i>SF3B1</i> patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-<i>SF3B1</i> primary CD34<sup>+</sup> cells and reduced mutant cell numbers in colony-forming assays. In contrast, normal hematopoietic progenitor cells were unaffected. Altogether, we here define <i>UBA1</i><sup>ms</sup> as a novel therapeutic vulnerability in <i>SF3B1</i>-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-<i>SF3B1</i> treatments.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"24 1","pages":""},"PeriodicalIF":13.4000,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-025-02740-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
Title: Leukemia
Journal Overview:
Publishes high-quality, peer-reviewed research
Covers all aspects of research and treatment of leukemia and allied diseases
Includes studies of normal hemopoiesis due to comparative relevance
Topics of Interest:
Oncogenes
Growth factors
Stem cells
Leukemia genomics
Cell cycle
Signal transduction
Molecular targets for therapy
And more
Content Types:
Original research articles
Reviews
Letters
Correspondence
Comments elaborating on significant advances and covering topical issues