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<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><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月26日

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  • 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

摘要

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.