title: The genome of chemorefractory chronic lymphocytic leukemia reveals frequent mutations of NOTCH1 and SF3B1.
abstract: Next-generation whole-exome sequencing has revealed two novel genes, namely NOTCH1 and SF3B1, whose mutations predict poor outcome and preferentially associate with chemorefractory chronic lymphocytic leukemia (CLL). Analysis of 539 CLL cases documents that NOTCH1 mutations i) represent one of the most frequent cancer gene mutations involved at presentation; ii) cluster with cases harboring trisomy 12 and tend to be mutually exclusive with TP53 disruption among genetic subgroups; iii) identify high-risk patients showing poor survival similar to that associated with TP53 abnormalities; and iv) exert a prognostic role independent of widely accepted clinical and genetic risk factors. Mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL, occur at a low rate at CLL presentation and have a minor role in Richter transformation, corroborating the notion that CLL histological shift is molecularly distinct from chemorefractory progression without the Richter transformation.
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Rasi
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Spina
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bruscaggin
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Monti
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cresta
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Famà
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Deambrogi
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Greco
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Fangazio
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ciardullo
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Piranda
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: G M
authors.initials: GM
authors.lastname: Casaluci
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University , Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Messina
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University , Rome, Italy.
authors.forename: I D
authors.initials: ID
authors.lastname: Giudice
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University , Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Chiaretti
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University , Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marinelli
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University , Rome, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Guarini
authors.affiliation: Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy; Fondazione Eleonora Lorillard Spencer Cenci, Sapienza University, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Foà
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont , Novara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Gaidano
keywords: NOTCH1; SF3B1; chronic lymphocytic leukemia; mutations; pathogenesis; prognostic markers