SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms Journal Article
| Authors: | Thier, J.; Hofmann, S.; Kirchhof, K. M.; Todisco, G.; Mortera-Blanco, T.; Lilienthal, I.; Kanellis, D. C.; Barbosa, I.; Björklund, A. C.; Deslauriers, A. G.; Bartek, J.; Herold, N.; Papaemmanuil, E.; Papapetrou, E. P.; Hellström-Lindberg, E.; Moura, P. L.; Lundin, V. |
| Article Title: | SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms |
| 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. |
| Keywords: | genes; classification; differentiation; expression; cells; sensitivity; mds; ubiquitin-activating enzyme; sf3b1 mutation; splicing events |
| Journal Title: | Leukemia |
| ISSN: | 0887-6924 |
| Publisher: | Nature Publishing Group |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| ACCESSION: | WOS:001556794900001 |
| DOI: | 10.1038/s41375-025-02740-1 |
| PROVIDER: | wos |
| Notes: | Article; Early Access -- Source: Wos |
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