Blood Journal
Leading the way in experimental and clinical research in hematology

Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness

  1. Davide Rossi1,
  2. Alessio Bruscaggin1,
  3. Valeria Spina1,
  4. Silvia Rasi1,
  5. Hossein Khiabanian2,
  6. Monica Messina3,
  7. Marco Fangazio1,
  8. Tiziana Vaisitti4,
  9. Sara Monti1,
  10. Sabina Chiaretti5,
  11. Anna Guarini5,
  12. Ilaria Del Giudice5,
  13. Michaela Cerri1,
  14. Stefania Cresta1,
  15. Clara Deambrogi1,
  16. Ernesto Gargiulo1,
  17. Valter Gattei6,
  18. Francesco Forconi7,
  19. Francesco Bertoni8,
  20. Silvia Deaglio4,
  21. Raul Rabadan2,
  22. Laura Pasqualucci3,
  23. Robin Foà5,
  24. Riccardo Dalla-Favera3,*, and
  25. Gianluca Gaidano1
  1. 1 Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;
  2. 2 Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, United States;
  3. 3 Institute of Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, United States;
  4. 4 Department of Genetics, Biology and Biochemistry and Human Genetics Foundation, University of Turin, Turin, Italy;
  5. 5 Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;
  6. 6 Clinical and Experimental Onco-Hematology, CRO, IRCCS, Aviano, Italy;
  7. 7 Division of Hematology, University of Siena, Siena, Italy;
  8. 8 Oncology Institute of Southern Switzerland - IOSI, Bellinzona, Switzerland
  1. * Corresponding author; email: rd10{at}


The genetic lesions identified in chronic lymphocytic leukemia (CLL) do not entirely recapitulate the disease pathogenesis and the development of serious complications, such as chemorefractoriness. While investigating the coding genome of fludarabine-refractory CLL, we observed that mutations of SF3B1, encoding a splicing factor and representing a critical component of the cell spliceosome, were recurrent in 10/59 (17%) fludarabine-refractory cases, with a frequency significantly higher than that observed in a consecutive CLL cohort sampled at diagnosis (17/301, 5%; p=.002). Mutations were somatically acquired, were generally represented by missense nucleotide changes, clustered in selected HEAT repeats of the SF3B1 protein, recurrently targeted three hotspots (codons 662, 666 and 700), and predicted poor prognosis. In fludarabine-refractory CLL, SF3B1 mutations and TP53 disruption distributed in a mutually exclusive fashion (p=.046). The identification of SF3B1 mutations points to splicing regulation as a novel pathogenetic mechanism of potential clinical relevance in CLL.

  • Submitted August 12, 2011.
  • Accepted October 18, 2011.