Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness.
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.
Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
Davide
D
Rossi
Alessio
A
Bruscaggin
Valeria
V
Spina
Silvia
S
Rasi
Hossein
H
Khiabanian
Monica
M
Messina
Marco
M
Fangazio
Tiziana
T
Vaisitti
Sara
S
Monti
Sabina
S
Chiaretti
Anna
A
Guarini
Ilaria
I
Del Giudice
Michaela
M
Cerri
Stefania
S
Cresta
Clara
C
Deambrogi
Ernesto
E
Gargiulo
Valter
V
Gattei
Francesco
F
Forconi
Francesco
F
Bertoni
Silvia
S
Deaglio
Raul
R
Rabadan
Laura
L
Pasqualucci
Robin
R
Foà
Riccardo
R
Dalla-Favera
Gianluca
G
Gaidano
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D017381:Spliceosomes / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D000970:Antineoplastic Agents; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; D016159:Tumor Suppressor Protein p53; D014740:Vidarabine; C024352:fludarabine