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Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders

Leukemia volume 26, pages 2447–2454 (2012)Cite this article

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Abstract

In humans, the majority of all protein-coding transcripts contain introns that are removed by mRNA splicing carried out by spliceosomes. Mutations in the spliceosome machinery have recently been identified using whole-exome/genome technologies in myelodysplastic syndromes (MDS) and in other hematological disorders. Alterations in splicing factor 3 subunit b1 (SF3b1) were the first spliceosomal mutations described, immediately followed by identification of other splicing factor mutations, including U2 small nuclear RNA auxillary factor 1 (U2AF1) and serine arginine-rich splicing factor 2 (SRSF2). SF3b1/U2AF1/SRSF2 mutations occur at varying frequencies in different disease subtypes, each contributing to differences in survival outcomes. However, the exact functional consequences of these spliceosomal mutations in the pathogenesis of MDS and other hematological malignancies remain largely unknown and subject to intense investigation. For SF3b1, a gain of function mutation may offer the promise of new targeted therapies for diseases that carry this molecular abnormality that can potentially lead to cure. This review aims to provide a comprehensive overview of the emerging role of the spliceosome machinery in the biology of MDS/hematological disorders with an emphasis on the functional consequences of mutations, their clinical significance, and perspectives on how they may influence our understanding and management of diseases affected by these mutations.

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Acknowledgements

We thank Dr K Koide from the University of Pittsburgh, PA for providing meayamycin and for sharing his expertise. We also thank Dr H Koseki from Riken, Japan for giving us the access to the SF3b1 heterozygous mice. This work was supported by the Cleveland Clinic Seed Support (RVT).

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    V Visconte, H Makishima, J P Maciejewski & R V Tiu

  2. Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    J P Maciejewski & R V Tiu

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  1. V Visconte
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Correspondence to R V Tiu.

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Visconte, V., Makishima, H., Maciejewski, J. et al. Emerging roles of the spliceosomal machinery in myelodysplastic syndromes and other hematological disorders. Leukemia 26, 2447–2454 (2012). https://doi.org/10.1038/leu.2012.130

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