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

Davide Rossi, Alessio Bruscaggin, Valeria Spina, Silvia Rasi, Hossein Khiabanian, Monica Messina, Marco Fangazio, Tiziana Vaisitti, Sara Monti, Sabina Chiaretti, Anna Guarini, Ilaria Del Giudice, Michaela Cerri, Stefania Cresta, Clara Deambrogi, Ernesto Gargiulo, Valter Gattei, Francesco Forconi, Francesco Bertoni, Silvia Deaglio, Raul Rabadan, Laura Pasqualucci, Robin Foà, Riccardo Dalla-Favera and Gianluca Gaidano


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.