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Background <p><i>SF3B1</i> spliceosome mutations are among the most common genetic lesions in myelodysplastic neoplasms (MDS). The canonical hotspot K700E variant is generally associated with a favorable prognosis, whereas the impact of other recurrent variants is poorly defined. We investigated the clinical, transcriptomic, and functional consequences of distinct <i>SF3B1</i> mutations in MDS patients and isogenic cell models. </p> Methods <p>Clinical data from 121 <i>SF3B1</i>-mutated MDS patients were analyzed. RNA sequencing was performed on CD34⁺ patient bone marrow cells and CRISPR-engineered NALM-6 lines harboring individual <i>SF3B1</i> variants. Comprehensive profiling of splicing, gene expression, and mitochondrial bioenergetic parameters was performed. </p> Results <p>Compared with K700E, the K666 variant was associated with shorter progression-free survival, distinct splicing abnormalities, and a higher frequency of retained introns, showing partial overlap with the H662 variant. Mitochondria-related genes were frequently mis-spliced and differentially expressed in K666-variant cells. In isogenic models, reduced complex IV activity and marked OXPHOS impairment were observed, with the most pronounced effects seen in K666N. Overall, <i>SF3B1</i> variants confer heterogeneous biological and clinical effects. The K666N variant, in particular, is associated with adverse prognosis and profound bioenergetic dysfunction. </p> Conclusions <p>These results support a refined view of <i>SF3B1</i>-mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.</p>

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Variant-specific SF3B1 mutations drive distinct splicing and mitochondrial dysfunction in myelodysplastic neoplasms

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Andrea Hruštincová,
  • Iva Trsová,
  • David Kundrát,
  • Monika Beličková,
  • Monika Kaisrlíková,
  • Jitka Veselá,
  • Zdeněk Krejčík,
  • Alžběta Hlaváčková,
  • Jiří Suttnar,
  • Hana Štufková,
  • Nikol Volfová,
  • Hana Hansíková,
  • Tatiana Aghová,
  • Zuzana Zemanová,
  • Anna Jonášová,
  • Jaroslav Čermák,
  • Markéta Šťastná Marková,
  • Michaela Dostálová Merkerová

摘要

Background

SF3B1 spliceosome mutations are among the most common genetic lesions in myelodysplastic neoplasms (MDS). The canonical hotspot K700E variant is generally associated with a favorable prognosis, whereas the impact of other recurrent variants is poorly defined. We investigated the clinical, transcriptomic, and functional consequences of distinct SF3B1 mutations in MDS patients and isogenic cell models.

Methods

Clinical data from 121 SF3B1-mutated MDS patients were analyzed. RNA sequencing was performed on CD34⁺ patient bone marrow cells and CRISPR-engineered NALM-6 lines harboring individual SF3B1 variants. Comprehensive profiling of splicing, gene expression, and mitochondrial bioenergetic parameters was performed.

Results

Compared with K700E, the K666 variant was associated with shorter progression-free survival, distinct splicing abnormalities, and a higher frequency of retained introns, showing partial overlap with the H662 variant. Mitochondria-related genes were frequently mis-spliced and differentially expressed in K666-variant cells. In isogenic models, reduced complex IV activity and marked OXPHOS impairment were observed, with the most pronounced effects seen in K666N. Overall, SF3B1 variants confer heterogeneous biological and clinical effects. The K666N variant, in particular, is associated with adverse prognosis and profound bioenergetic dysfunction.

Conclusions

These results support a refined view of SF3B1-mutated MDS as a biologically heterogeneous entity and suggest that variant-specific mitochondrial vulnerabilities may represent exploitable targets for precision-based therapeutic strategies.