Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Diop, Fary; Moia, Riccardo; Favini, Chiara; Spaccarotella, Elisa; De Paoli, Lorenzo; Bruscaggin, Alessio; Spina, Valeria; Terzi-di-Bergamo, Lodovico; Arruga, Francesca; Tarantelli, Chiara; Deambrogi, Clara; Rasi, Silvia; Adhinaveni, Ramesh; Patriarca, Andrea; Favini, Simone; Sagiraju, Sruthi; Jabangwe, Clive; Kodipad, Ahad A.; Peroni, Denise; Mauro, Francesca R.; Del Giudice, Ilaria; Forconi, Francesco; Cortelezzi, Agostino; Zaja, Francesco; Bomben, Riccardo; Rossi, Francesca Maria; Visco, Carlo; Chiarenza, Annalisa; Rigolin, Gian Matteo; Marasca, Roberto; Coscia, Marta; Perbellini, Omar; Tedeschi, Alessandra; Laurenti, Luca; Motta, Marina; Donaldson, David; Weir, Phil; Mills, Ken; Thornton, Patrick; Lawless, Sarah; Bertoni, Francesco; Del Poeta, Giovanni; Cuneo, Antonio; Follenzi, Antonia; Gattei, Valter; Boldorini, Renzo Luciano; Catherwood, Mark; Deaglio, Silvia; Foà, Robin; Gaidano, Gianluca; Rossi, Davide

doi:10.3324/haematol.2019.219550

Back

Journal article

Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Diop, Fary Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Moia, Riccardo Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Favini, Chiara Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Spaccarotella, Elisa Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
De Paoli, Lorenzo Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Bruscaggin, Alessio Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
Spina, Valeria Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
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
Arruga, Francesca Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
Tarantelli, Chiara Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Deambrogi, Clara Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Rasi, Silvia Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Adhinaveni, Ramesh Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Patriarca, Andrea Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Favini, Simone Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Sagiraju, Sruthi Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Jabangwe, Clive Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Kodipad, Ahad A. Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Peroni, Denise Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Mauro, Francesca R. Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Del Giudice, Ilaria Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
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
Cortelezzi, Agostino Department of Hematology Oncology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Italy
Zaja, Francesco Clinica Ematologica, DAME, University of Udine, Italy
Bomben, Riccardo Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
Rossi, Francesca Maria Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
Visco, Carlo Department of Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy
Chiarenza, Annalisa Division of Hematology, Azienda Ospedaliera Universitaria Policlinico-OVE, Catania, Italy
Rigolin, Gian Matteo Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy
Marasca, Roberto Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Italy
Coscia, Marta Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza and University of Turin, Italy
Perbellini, Omar Section of Hematology, Department of Medicine, University of Verona, Italy
Tedeschi, Alessandra Department of Oncology/Haematology, Niguarda Cancer Center, Niguarda Ca Granda Hospital, Milan, Italy
Laurenti, Luca Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
Motta, Marina Department of Hematology, Spedali Civili, Brescia, Italy
Donaldson, David Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
Weir, Phil Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
Mills, Ken Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Northern Ireland, UK
Thornton, Patrick Department of Haematology, Beaumont Hospital, Dublin, Ireland
Lawless, Sarah Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
Bertoni, Francesco Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
Del Poeta, Giovanni Department of Hematology, Tor Vergata University, Rome, Italy
Cuneo, Antonio Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Italy
Follenzi, Antonia Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
Gattei, Valter Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
Boldorini, Renzo Luciano Department of Pathology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
Catherwood, Mark Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
Deaglio, Silvia Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
Foà, Robin Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
Gaidano, Gianluca Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
Rossi, Davide Institute of Oncology Research (IOR), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

01.02.2020

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.

Language