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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.