Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
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Diop, Fary
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Moia, Riccardo
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Favini, Chiara
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Spaccarotella, Elisa
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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De Paoli, Lorenzo
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Bruscaggin, Alessio
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
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Spina, Valeria
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
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Terzi-di-Bergamo, Lodovico
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
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Arruga, Francesca
Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
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Tarantelli, Chiara
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Deambrogi, Clara
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Rasi, Silvia
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Adhinaveni, Ramesh
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Patriarca, Andrea
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Favini, Simone
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Sagiraju, Sruthi
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Jabangwe, Clive
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Kodipad, Ahad A.
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Peroni, Denise
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Mauro, Francesca R.
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
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Del Giudice, Ilaria
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
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Forconi, Francesco
Cancer Sciences Unit, Southampton Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centre, University of Southampton, UK - Division of Hematology, University of Siena, Italy
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Cortelezzi, Agostino
Department of Hematology Oncology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Italy
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Zaja, Francesco
Clinica Ematologica, DAME, University of Udine, Italy
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Bomben, Riccardo
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
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Rossi, Francesca Maria
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
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Visco, Carlo
Department of Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy
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Chiarenza, Annalisa
Division of Hematology, Azienda Ospedaliera Universitaria Policlinico-OVE, Catania, Italy
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Rigolin, Gian Matteo
Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy
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Marasca, Roberto
Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Italy
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Coscia, Marta
Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza and University of Turin, Italy
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Perbellini, Omar
Section of Hematology, Department of Medicine, University of Verona, Italy
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Tedeschi, Alessandra
Department of Oncology/Haematology, Niguarda Cancer Center, Niguarda Ca Granda Hospital, Milan, Italy
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Laurenti, Luca
Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
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Motta, Marina
Department of Hematology, Spedali Civili, Brescia, Italy
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Donaldson, David
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
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Weir, Phil
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
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Mills, Ken
Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Northern Ireland, UK
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Thornton, Patrick
Department of Haematology, Beaumont Hospital, Dublin, Ireland
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Lawless, Sarah
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
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Bertoni, Francesco
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Del Poeta, Giovanni
Department of Hematology, Tor Vergata University, Rome, Italy
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Cuneo, Antonio
Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy
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Follenzi, Antonia
Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
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Gattei, Valter
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
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Boldorini, Renzo Luciano
Department of Pathology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
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Catherwood, Mark
Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
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Deaglio, Silvia
Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
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Foà, Robin
Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
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Gaidano, Gianluca
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
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Rossi, Davide
Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
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Published in:
- Haematologica. - 2020, vol. 105, no. 2, p. 448-456
English
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
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https://n2t.net/ark:/12658/srd1319160
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