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A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages

Leukemia volume 28, pages 1355–1357 (2014)Cite this article

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The RNA maturation is an important and complex biological process. It requires several small nuclear ribonucleoproteins (snRNPs) that comprise the two forms of spliceosomes. The major form of spliceosome (U2-type) is composed of U1, U2, U4/6 and U5 snRNPs, and catalyzes most splicing events in metazoans.1

Mutations of genes, such as SF3B1, SRSF2, U2AF1, ZRSR2, and to a lesser extent SF1, SF3A1, U2AF2 or PRPF40B, encoding spliceosome compounds have been found to occur at high frequencies in myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL).2, 3, 4 Subsequently, SF3B1 mutations were also found in solid tumors such as endometrial, lung, bladder, pancreatic and breast carcinomas and cutaneous melanomas.5 We and others also reported that 15–20% of uveal melanoma (UM) carry SF3B1 mutations.6, 7, 8 SF3B1 (splicing factor 3 B subunit 1, also named SF3B155) is a central compound the U2 snRNP complex in direct contact with the branch site of the pre-mRNA. SF3B1 contains 22 HEAT repeats (Huntingtin, Elongation factor 3, protein phosphatase 2A, Targets of rapamycin 1). Major hotspots of missense mutations of SF3B1 target one of the HEAT repeats at positions R625, K666 and K700, with variability according to diseases, R625 and K700 mutations being the most prevalent in UM and hematologic disorders, respectively. Prognosis value of these mutations vary according to diseases, SF3B1 mutations are associated with poor outcomes in CLL and favorable outcomes in UM.9 SF3B1 mutations are especially associated with the refractory anemia with excess of ring sideroblasts (RARS), a mild form of MDS with little impact on patient’s survival. Consequences of these mutations on splicing are less clear. Aberrant splicing associated with SF3B1 was reported by two landmark publications.2, 3 However, little overlap was found between MDS and CLL. Furthermore, Harbour et al.6 found no splicing effect of SF3B1 mutations in a series of UM patients analyzed by RNA-seq. By combining exon array and RNA-seq analyzes, we recently reported alternative transcripts of eight genes statistically associated with SF3B1 R625 mutations and linked to various RNA processing mechanisms: alternative terminal exons (UQCC, ADAM12, GAS8), alternative 3′ acceptor splice sites (CRNDE, ANKHD1), alternative cassette exons (GUSBP1), alternative first exon (F8) and intron retention (ABCC5).7

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Acknowledgements

We thank Pierre de la Grange for splicing analysis of UM and design of QPCR primers, Odette Mariani and colleagues for UM samples, Audrey Gauthier and Elena Mylonas for assembly and characterization of patients.

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Authors and Affiliations

  1. Institut Curie, Centre de Recherche, Paris, France

    D Gentien, B Albaud, A Rapinat, A G Dumont, T Popova, S Roman-Roman & M-H Stern

  2. Translational Research Department, Paris, France

    D Gentien, B Albaud, A Rapinat & S Roman-Roman

  3. Département Développement, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Service d’Hématologie Biologique, Institut Cochin, Reproduction, Cancer, INSERM U1016 CNRS UMR8104, and Université Paris Descartes, Paris, France

    O Kosmider & M Fontenay

  4. Service d'Hématologie Biologique, Hôpital Pitié-Salpêtrière and INSERM U872, UPMC, Paris, France

    F Nguyen-Khac

  5. INSERM U830, Paris, France

    A G Dumont, T Popova & M-H Stern

  6. The Cancer Research UK Manchester Institute, Manchester, UK

    R Marais

  7. INSERM U985, Institut Gustave Roussy, Villejuif, France and Université Paris-Sud, Orsay, France

    F Damm & O A Bernard

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  1. D Gentien
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Correspondence to M-H Stern.

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Gentien, D., Kosmider, O., Nguyen-Khac, F. et al. A common alternative splicing signature is associated with SF3B1 mutations in malignancies from different cell lineages. Leukemia 28, 1355–1357 (2014). https://doi.org/10.1038/leu.2014.28

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