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

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

Research output: Contribution to journalArticle

192 Citations (Scopus)

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-κB 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 fludarabinerefractory 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-κB, biochemical studies revealed the presence of constitutive noncanonical NF-κB activation in fludarabinerefractory CLL patients harboring molecular lesions of BIRC3. These data identify BIRC3 disruption as a recurrent genetic lesion of high-riskCLL devoid of TP53 abnormalities.

Original languageEnglish
Pages (from-to)2854-2862
Number of pages9
JournalBlood
Volume119
Issue number12
DOIs
Publication statusPublished - Mar 22 2012

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B-Cell Chronic Lymphocytic Leukemia
Refractory materials
Genes
Chemical activation
Cells
Actuarial Analysis
Lymphocytosis
Gene Deletion
fludarabine
B-Lymphocytes
Phenotype
Mutation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Rossi, D., Fangazio, M., Rasi, S., Vaisitti, T., Monti, S., Cresta, S., ... Gaidano, G. (2012). Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. Blood, 119(12), 2854-2862. https://doi.org/10.1182/blood-2011-12-395673

Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. / 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; Gaidano, Gianluca.

In: Blood, Vol. 119, No. 12, 22.03.2012, p. 2854-2862.

Research output: Contribution to journalArticle

Rossi, D, Fangazio, M, Rasi, S, Vaisitti, T, Monti, S, Cresta, S, Chiaretti, S, Del Giudice, I, Fabbri, G, Bruscaggin, A, Spina, V, Deambrogi, C, Marinelli, M, Famà, R, Greco, M, Daniele, G, Forconi, F, Gattei, V, Bertoni, F, Deaglio, S, Pasqualucci, L, Guarini, A, Dalla-Favera, R, Foà, R & Gaidano, G 2012, 'Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia', Blood, vol. 119, no. 12, pp. 2854-2862. https://doi.org/10.1182/blood-2011-12-395673
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 ; Gaidano, Gianluca. / Disruption of BIRC3 associates with fludarabine chemorefractoriness in TP53 wild-type chronic lymphocytic leukemia. In: Blood. 2012 ; Vol. 119, No. 12. pp. 2854-2862.
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AU - Monti, Sara

AU - Cresta, Stefania

AU - Chiaretti, Sabina

AU - Del Giudice, Ilaria

AU - Fabbri, Giulia

AU - Bruscaggin, Alessio

AU - Spina, Valeria

AU - Deambrogi, Clara

AU - Marinelli, Marilisa

AU - Famà, Rosella

AU - Greco, Mariangela

AU - Daniele, Giulia

AU - Forconi, Francesco

AU - Gattei, Valter

AU - Bertoni, Francesco

AU - Deaglio, Silvia

AU - Pasqualucci, Laura

AU - Guarini, Anna

AU - Dalla-Favera, Riccardo

AU - Foà, Robin

AU - Gaidano, Gianluca

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