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

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

来源：Blood, 2011, 118(26): 6904-6908.

DOI：10.1182/blood-2011-08-373159

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 of 59 (17%) fludarabine-refractory cases, with a frequency significantly greater 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 3 hotspots (codons 662, 666, and 700), and were predictive of a 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. (Blood. 2011;118(26):6904-6908)

• 出版日期2011-12-22