Blood Journal
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Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes

  1. Frederik Damm1,2,
  2. Olivier Kosmider37,
  3. Véronique Gelsi-Boyer8,9,
  4. Aline Renneville10,
  5. Nadine Carbuccia8,9,
  6. Claire Hidalgo-Curtis11,12,
  7. Véronique Della Valle1,2,13,
  8. Lucile Couronné1,2,13,
  9. Laurianne Scourzic1,2,13,
  10. Virginie Chesnais47,
  11. Agnes Guerci-Bresler14,
  12. Bohrane Slama15,
  13. Odile Beyne-Rauzy16,
  14. Aline Schmidt-Tanguy17,
  15. Aspasia Stamatoullas-Bastard18,
  16. François Dreyfus19,
  17. Thomas Prébet8,9,20,
  18. Stéphane de Botton21,
  19. Norbert Vey8,9,20,
  20. Michael A. Morgan22,
  21. Nicholas C. P. Cross11,12,
  22. Claude Preudhomme10,
  23. Daniel Birnbaum8,9,
  24. Olivier A. Bernard1,2,13, and
  25. Michaela Fontenay37
  26. on behalf of the Groupe Francophone des Myélodysplasies
  1. 1Institut Gustave Roussy, Villejuif, France;
  2. 2Inserm U985, Villejuif, France;
  3. 3Assistance Publique–Hôpitaux de Paris (AP-HP), Service d'Hématologie Biologique, Hôpital Broca-Cochin-Hôtel-Dieu, Paris, France;
  4. 4Département d'Immunologie et Hématologie, Institut Cochin, Paris, France;
  5. 5Inserm U1016, Paris, France;
  6. 6Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Paris, France;
  7. 7Université Paris Descartes, Paris France;
  8. 8Centre de Recherche en Cancérologie de Marseille, Département d'Oncologie Moléculaire, Unité Mixte de Recherche 1068 Inserm, Institut Paoli-Calmettes, Marseille, France;
  9. 9Université Aix-Marseille, Marseille, France;
  10. 10Laboratoire d'Hématologie, Centre Hospitalier Regional Universitaire, Lille, France;
  11. 11Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
  12. 12Wessex Regional Genetics Laboratory, Salisbury, United Kingdom;
  13. 13Université Paris-Sud, Orsay, France;
  14. 14Service d'Hématologie et de Médecine Interne, Centre Hospitalier Universitaire Nancy, Nancy, France;
  15. 15Service de Médecine Interne, Centre Hospitalier Avignon, Avignon, France;
  16. 16Service de Médecine Interne, Centre Hospitalier Universitaire Purpan, Toulouse, France;
  17. 17Service des Maladies du Sang, Centre Hospitalier Universitaire Angers, Université d'Angers, Inserm U892, Angers, France;
  18. 18Département d'Hématologie, Centre de Lutte Contre le Cancer Henri Becquerel, Rouen, France;
  19. 19AP-HP, Hôpital Cochin, Paris;
  20. 20Département d'Hématologie, Institut Paoli-Calmette, Marseille, France;
  21. 21Service d'Hématologie, Institut Gustave Roussy, Villejuif, France; and
  22. 22Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany


A cohort of MDS patients was examined for mutations affecting 4 splice genes (SF3B1, SRSF2, ZRSR2, and U2AF35) and evaluated in the context of clinical and molecular markers. Splice gene mutations were detected in 95 of 221 patients. These mutations were mutually exclusive and less likely to occur in patients with complex cytogenetics or TP53 mutations. SF3B1mut patients presented with lower hemoglobin levels, increased WBC and platelet counts, and were more likely to have DNMT3A mutations. SRSF2mut patients clustered in RAEB-1 and RAEB-2 subtypes and exhibited pronounced thrombocytopenias. ZRSR2mut patients clustered in International Prognostic Scoring System intermediate-1 and intermediate-2 risk groups, had higher percentages of bone marrow blasts, and more often displayed isolated neutropenias. SRSF2 and ZRSR2 mutations were more common in TET2mut patients. U2AF35mut patients had an increased prevalence of chromosome 20 deletions and ASXL1 mutations. Multivariate analysis revealed an inferior overall survival and a higher AML transformation rate for the genotype ZRSR2mut/TET2wt (overall survival: hazard ratio = 3.3; 95% CI, 1.4-7.7; P = .006; AML transformation: hazard ratio = 3.6; 95% CI, 2-4.2; P = .026). Our results demonstrate that splice gene mutations are among the most frequent molecular aberrations in myelodysplastic syndrome, define distinct clinical phenotypes, and show preferential associations with mutations targeting transcriptional regulation.

  • Submitted December 28, 2011.
  • Accepted February 13, 2012.
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