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

Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness
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.
0006-4971
6904-6908
Rossi, Davide
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Bruscaggin, Alessio
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Spina, Valeria
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Rasi, Silvia
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Khiabanian, Hossein
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Messina, Monica
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Fangazio, Marco
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Vaisitti, Tiziana
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Monti, Sara
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Chiaretti, Sabina
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Guarini, Anna
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Del Giudice, Ilaria
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Cerri, Michaela
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Cresta, Stefania
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Deambrogi, Clara
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Gargiulo, Ernesto
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Gattei, Valter
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Forconi, Francesco
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Bertoni, Francesco
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Deaglio, Silvia
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Rabadan, Raul
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Pasqualucci, Laura
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Foà, Robin
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Dalla-Favera, Riccardo
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Gaidano, Gianluca
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Rossi, Davide
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Bruscaggin, Alessio
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Spina, Valeria
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Rasi, Silvia
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Khiabanian, Hossein
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Messina, Monica
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Fangazio, Marco
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Vaisitti, Tiziana
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Monti, Sara
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Chiaretti, Sabina
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Guarini, Anna
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Del Giudice, Ilaria
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Cerri, Michaela
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Cresta, Stefania
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Deambrogi, Clara
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Gargiulo, Ernesto
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Gattei, Valter
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Forconi, Francesco
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Bertoni, Francesco
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Deaglio, Silvia
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Rabadan, Raul
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Pasqualucci, Laura
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Foà, Robin
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Dalla-Favera, Riccardo
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Gaidano, Gianluca
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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, Foà, Robin, Dalla-Favera, Riccardo and Gaidano, Gianluca (2011) Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia: association with progression and fludarabine-refractoriness. Blood, 118 (26), 6904-6908. (doi:10.1182/blood-2011-08-373159). (PMID:22039264)

Record type: Article

Abstract

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.

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More information

e-pub ahead of print date: 28 October 2011
Published date: 22 December 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 358117
URI: http://eprints.soton.ac.uk/id/eprint/358117
ISSN: 0006-4971
PURE UUID: a0947c57-a4cd-4d97-a15b-6b2b6d941ce5
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 04 Oct 2013 11:22
Last modified: 15 Mar 2024 03:40

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Contributors

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

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