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Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia

Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia
Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia
The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-?B signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-?B, biochemical studies revealed the presence of constitutive noncanonical NF-?B activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities.
0006-4971
2854-2862
Rossi, Davide
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Fangazio, Marco
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Rasi, Silvia
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Vaisitti, Tiziana
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Monti, Sara
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Cresta, Stefania
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Chiaretti, Sabina
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Del Giudice, Ilaria
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Fabbri, Giulia
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Bruscaggin, Alessio
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Spina, Valeria
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Deambrogi, Clara
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Marinelli, Marilisa
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Famà, Rosella
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Greco, Mariangela
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Daniele, Giulia
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Forconi, Francesco
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Gattei, Valter
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Bertoni, Francesco
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Deaglio, Silvia
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Pasqualucci, Laura
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Guarini, Anna
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Dalla-Favera, Riccardo
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Foà, Robin
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Gaidano, Gianluca
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Rossi, Davide
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Fangazio, Marco
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Rasi, Silvia
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Vaisitti, Tiziana
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Monti, Sara
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Cresta, Stefania
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Chiaretti, Sabina
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Del Giudice, Ilaria
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Fabbri, Giulia
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Bruscaggin, Alessio
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Spina, Valeria
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Deambrogi, Clara
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Marinelli, Marilisa
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Famà, Rosella
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Greco, Mariangela
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Daniele, Giulia
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Forconi, Francesco
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Gattei, Valter
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Bertoni, Francesco
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Deaglio, Silvia
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Pasqualucci, Laura
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Guarini, Anna
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Dalla-Favera, Riccardo
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Foà, Robin
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Gaidano, Gianluca
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Rossi, Davide, Fangazio, Marco, Rasi, Silvia, Vaisitti, Tiziana, Monti, Sara, Cresta, Stefania, Chiaretti, Sabina, Del Giudice, Ilaria, Fabbri, Giulia, Bruscaggin, Alessio, Spina, Valeria, Deambrogi, Clara, Marinelli, Marilisa, Famà, Rosella, Greco, Mariangela, Daniele, Giulia, Forconi, Francesco, Gattei, Valter, Bertoni, Francesco, Deaglio, Silvia, Pasqualucci, Laura, Guarini, Anna, Dalla-Favera, Riccardo, Foà, Robin and Gaidano, Gianluca (2012) Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood, 119 (12), 2854-2862. (doi:10.1182/blood-2011-12-395673). (PMID:22308293)

Record type: Article

Abstract

The genetic lesions identified to date do not fully recapitulate the molecular pathogenesis of chronic lymphocytic leukemia (CLL) and do not entirely explain the development of severe complications such as chemorefractoriness. In the present study, BIRC3, a negative regulator of noncanonical NF-?B signaling, was investigated in different CLL clinical phases. BIRC3 lesions were absent in monoclonal B-cell lymphocytosis (0 of 63) and were rare in CLL at diagnosis (13 of 306, 4%). Conversely, BIRC3 disruption selectively affected 12 of 49 (24%) fludarabine-refractory CLL cases by inactivating mutations and/or gene deletions that distributed in a mutually exclusive fashion with TP53 abnormalities. In contrast to fludarabine-refractory CLL, progressive but fludarabine-sensitive patients were consistently devoid of BIRC3 abnormalities, suggesting that BIRC3 genetic lesions associate specifically with a chemorefractory phenotype. By actuarial analysis in newly diagnosed CLL (n = 306), BIRC3 disruption identified patients with a poor outcome similar to that associated with TP53 abnormalities and exerted a prognostic role that was independent of widely accepted clinical and genetic risk factors. Consistent with the role of BIRC3 as a negative regulator of NF-?B, biochemical studies revealed the presence of constitutive noncanonical NF-?B activation in fludarabine-refractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-risk CLL devoid of TP53 abnormalities.

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e-pub ahead of print date: 3 February 2012
Published date: 22 March 2012
Organisations: Cancer Sciences

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Local EPrints ID: 358110
URI: https://eprints.soton.ac.uk/id/eprint/358110
ISSN: 0006-4971
PURE UUID: 055e7ff2-4872-4792-95a7-e81654807d1f

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Date deposited: 04 Oct 2013 10:35
Last modified: 16 Jul 2019 21:21

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Contributors

Author: Davide Rossi
Author: Marco Fangazio
Author: Silvia Rasi
Author: Tiziana Vaisitti
Author: Sara Monti
Author: Stefania Cresta
Author: Sabina Chiaretti
Author: Ilaria Del Giudice
Author: Giulia Fabbri
Author: Alessio Bruscaggin
Author: Valeria Spina
Author: Clara Deambrogi
Author: Marilisa Marinelli
Author: Rosella Famà
Author: Mariangela Greco
Author: Giulia Daniele
Author: Valter Gattei
Author: Francesco Bertoni
Author: Silvia Deaglio
Author: Laura Pasqualucci
Author: Anna Guarini
Author: Riccardo Dalla-Favera
Author: Robin Foà
Author: Gianluca Gaidano

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