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SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications

Leukemia volume 26, pages 1137–1140 (2012)Cite this article

Myelodysplastic syndromes (MDS) are neoplastic diseases of the hematopoietic stem cell with a pronounced heterogeneity regarding morphology and clinical course.1 In order to understand the complex pathophysiology, many efforts have been made to unravel the molecular background of MDS. Mutations in several genes were identified in the last few years, including TET2,2 ASXL1,3 EZH2,4 IDH1,5, 6 DNMT3A,7 TEL/ETV6,8 RUNX18 and TP53.8 Some of these molecular aberrations provide prognostic information that allows further sub-classification and possibly risk-directed therapeutic intervention.8, 9 Recent studies using next-generation sequencing approaches identified previously unknown aberrations of the Splicing factor 3b, subunit 1 (SF3B1) in about 20% of MDS patients.10, 11, 12 The prevalence of SF3B1 mutations was up to 75% in the subgroup of MDS defined by the presence of ring sideroblasts (RS).10 SF3B1 is located at chromosomal band 2q33 and encodes a core component of the U2 small nuclear ribonucleoprotein complex (U2 snRNP). U2 snRNP is a part of the catalytic site of the spliceosome that processes pre-messenger RNA to mature mRNA and thus regulates the diversity of splice variants.13

To date, little is known about the clinical phenotype and prognostic implications of SF3B1 mutations in MDS. To address this question, the current study used direct sequencing to analyze the mutational hotspots of SF3B1 (exons 13–16) in a large series of 317 MDS patients comprising all subtypes of the WHO 2008 classification. Informed consent was obtained from all patients in accordance with the Declaration of Helsinki. This study was approved by the institutional review board of Hannover Medical School and the Paris Centre ethics committee. Cell samples were collected at the time of enrolment in multicenter clinical trials conducted either in Germany (n=193) or France (n=124). Treatment details for both cohorts have been published earlier.9, 14, 15 The statistical analyses were performed with the statistical software package SPSS 19.0 (SPSS Science, Chicago, IL, USA). Overall-survival and acute myeloid leukemia (AML) progression rates were similar with 5-year overall survival (OS) of 36% in the German vs 34% in the French cohort (P=0.45) and AML progression rates of 27.5% vs 21% (P=0.22), respectively.

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Acknowledgements

This study was supported by the Hannelore-Munke Fellowship and grant #109686 by the Deutsche Krebshilfe awarded to FD; HiLF grant from Hannover Medical School awarded to FT; association ‘Laurette Fugain’ (OAB and FD); grant ‘Direction de la recherche clinique AP-HP (PHRC MDS-04)’ and INCa translational research 2008 awarded to FM; grant No. DJCLS R 10/22 from the Deutsche-José-Carreras Leukämie-Stiftung e.V.; grant No. 109003 from the Deutsche Krebshilfe e.V; and grant No. M 47.1 from the H. W. & J. Hector Stiftung.

We thank the investigators of the German myelodysplastic study group and the Groupe Francophone des Myélodysplasies (Dr B Slama, Avignon; Dr Gardembas, Angers; Dr Dib, Angers; Dr Rose, Lille; Dr Cheze, Caen; Dr Ame, Strasbourg; Dr Gyan, Tours) for including patients, and Martin Wichmann, Kerstin Göhrlich, Lamya Slama, Gaelle Herledan and Julien Brard for technical assistance.

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Author notes

  1. F Damm, F Thol and O Kosmider: These authors contributed equally to this work

  2. M Fontenay and M Heuser: These authors have senior authorship

Authors and Affiliations

  1. Institut Gustave Roussy, Villejuif, France

    F Damm, S de Botton & O A Bernard

  2. INSERM, U985, Villejuif, France

    F Damm & O A Bernard

  3. Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    F Thol, S Kade, P Löffeld, A Ganser & M Heuser

  4. Assistance Publique-Hôpitaux de Paris, Service d’Hématologie Biologique, Hôpital Broca-Cochin-Hôtel-Dieu, Paris, France

    O Kosmider & M Fontenay

  5. AP-HP UF Hématologie, Université Paris Descartes, Institut Cochin Inserm U1016, Paris, France

    F Dreyfus

  6. Département d’hématologie, CLCC Henri Becquerel, Rouen, France

    A Stamatoullas-Bastard

  7. Service des Maladies du sang, CHU Angers, France

    A Tanguy-Schmidt

  8. Service de Médecine Interne, CHU Purpan, Toulouse, France

    O Beyne-Rauzy

  9. Département d’hématologie et Médecine Interne, CHU Nancy, France

    A Guerci-Bresler

  10. Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

    G Göhring & B Schlegelberger

  11. Université Paris-Sud, Orsay, France

    O A Bernard

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  1. F Damm
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Correspondence to F Damm.

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Damm, F., Thol, F., Kosmider, O. et al. SF3B1 mutations in myelodysplastic syndromes: clinical associations and prognostic implications. Leukemia 26, 1137–1140 (2012). https://doi.org/10.1038/leu.2011.321

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