SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms

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 SF3B1<sup>K700E</sup> and SF3B1<sup>WT</sup> 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 SF3B1<sup>K700E</sup>-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 (UBA1<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 UBA1<sup>ms</sup> in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 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 UBA1<sup>ms</sup> as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.

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Publication Details

Journal
Leukemia
Published
2025-08-26
DOI
https://doi.org/10.1038/s41375-025-02740-1
Citations
3
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
5.31

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article

SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms

Ann-Charlotte Björklund, Nikolas Herold, Indira Barbosa, Ingrid Lilienthal et al.
3 citations
Leukemia
Acute Myeloid Leukemia Research
5.31
article

SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms

Ann-Charlotte Björklund, Nikolas Herold, Indira Barbosa, Ingrid Lilienthal, Eva Hellström‐Lindberg, Katharina Miria Kirchhof, Dimitris C. Kanellis, Vanessa Lundin, Pedro Luís Moura, André G. Deslauriers, Teresa Mortera‐Blanco, Gabriele Todisco, Eirini P. Papapetrou, Elli Papaemmanuil, Jiří Bártek, Jonas Thier, Sophia Hofmann
article en
3 citations

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 SF3B1<sup>K700E</sup> and SF3B1<sup>WT</sup> 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 SF3B1<sup>K700E</sup>-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 (UBA1<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 UBA1<sup>ms</sup> in MDS-SF3B1 patients, absent in other splicing factor-mutated MDS cases or healthy controls. TAK-243 selectively targeted MDS-SF3B1 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 UBA1<sup>ms</sup> as a novel therapeutic vulnerability in SF3B1-mutant cells, introducing UBA1 inhibition as a potential avenue for future MDS-SF3B1 treatments.

LeukemiaVol. 39(11)
Memorial Sloan Kettering Cancer Center (US), Karolinska University Hospital (SE), Humanitas University (IT), Novo Nordisk (Denmark) (DK), Science for Life Laboratory (SE), Karolinska Institutet (SE), Integrated Cardio Metabolic Centre (SE), Danish Cancer Society (DK), Icahn School of Medicine at Mount Sinai (US)
Cancerfonden, Lunds Universitet, Karolinska Institutet, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Science for Life Laboratory, Dr Åke Olssons Stiftelse för Haematologisk Forskning
Openalex Percentile: Top 4%
Acute Myeloid Leukemia Research
5.31
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