Haematologica (Feb 2020)
Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
- Fary Diop,
- Riccardo Moia,
- Chiara Favini,
- Elisa Spaccarotella,
- Lorenzo De Paoli,
- Alessio Bruscaggin,
- Valeria Spina,
- Lodovico Terzi-di-Bergamo,
- Francesca Arruga,
- Chiara Tarantelli,
- Clara Deambrogi,
- Silvia Rasi,
- Ramesh Adhinaveni,
- Andrea Patriarca,
- Simone Favini,
- Sruthi Sagiraju,
- Clive Jabangwe,
- Ahad A. Kodipad,
- Denise Peroni,
- Francesca R. Mauro,
- Ilaria Del Giudice,
- Francesco Forconi,
- Agostino Cortelezzi,
- Francesco Zaja,
- Riccardo Bomben,
- Francesca Maria Rossi,
- Carlo Visco,
- Annalisa Chiarenza,
- Gian Matteo Rigolin,
- Roberto Marasca,
- Marta Coscia,
- Omar Perbellini,
- Alessandra Tedeschi,
- Luca Laurenti,
- Marina Motta,
- David Donaldson,
- Phil Weir,
- Ken Mills,
- Patrick Thornton,
- Sarah Lawless,
- Francesco Bertoni,
- Giovanni Del Poeta,
- Antonio Cuneo,
- Antonia Follenzi,
- Valter Gattei,
- Renzo Luciano Boldorini,
- Mark Catherwood,
- Silvia Deaglio,
- Robin Foà,
- Gianluca Gaidano°,
- Davide Rossi°
Affiliations
- Fary Diop
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Riccardo Moia
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Chiara Favini
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Elisa Spaccarotella
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Lorenzo De Paoli
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Alessio Bruscaggin
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
- Valeria Spina
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
- Lodovico Terzi-di-Bergamo
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
- Francesca Arruga
- Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
- Chiara Tarantelli
- Università della Svizzera Italiana, Institute of Oncology Research, Bellinzona, Switzerland
- Clara Deambrogi
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Silvia Rasi
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Ramesh Adhinaveni
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Andrea Patriarca
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Simone Favini
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Sruthi Sagiraju
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Clive Jabangwe
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Ahad A. Kodipad
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Denise Peroni
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Francesca R. Mauro
- Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
- Ilaria Del Giudice
- Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
- Francesco Forconi
- Cancer Sciences Unit, Southampton Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK;Division of Hematology, University of Siena, Siena, Italy
- Agostino Cortelezzi
- Department of Hematology Oncology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy
- Francesco Zaja
- Clinica Ematologica, DAME, University of Udine, Udine, Italy
- Riccardo Bomben
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
- Francesca Maria Rossi
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
- Carlo Visco
- Department of Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy
- Annalisa Chiarenza
- Division of Hematology, Azienda Ospedaliera Universitaria Policlinico-OVE, Catania, Italy
- Gian Matteo Rigolin
- Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Ferrara, Italy
- Roberto Marasca
- Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
- Marta Coscia
- Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza and University of Turin, Turin, Italy
- Omar Perbellini
- Section of Hematology, Department of Medicine, University of Verona, Verona, Italy
- Alessandra Tedeschi
- Department of Oncology/Haematology, Niguarda Cancer Center, Niguarda Ca Granda Hospital, Milan, Italy
- Luca Laurenti
- Fondazione Policlinico Universitario A. Gemelli, Rome, Italy
- Marina Motta
- Department of Hematology, Spedali Civili, Brescia, Italy
- David Donaldson
- Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Phil Weir
- Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Ken Mills
- Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Belfast, Northern Ireland, UK
- Patrick Thornton
- Department of Haematology, Beaumont Hospital, Dublin, Ireland
- Sarah Lawless
- Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Francesco Bertoni
- Università della Svizzera Italiana, Institute of Oncology Research, Bellinzona, Switzerland
- Giovanni Del Poeta
- Department of Hematology, Tor Vergata University, Rome, Italy
- Antonio Cuneo
- Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Ferrara, Italy
- Antonia Follenzi
- Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
- Valter Gattei
- Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy
- Renzo Luciano Boldorini
- Department of Pathology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy
- Mark Catherwood
- Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
- Silvia Deaglio
- Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy
- Robin Foà
- Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
- Gianluca Gaidano°
- Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
- Davide Rossi°
- Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
- DOI
- https://doi.org/10.3324/haematol.2019.219550
- Journal volume & issue
-
Vol. 105,
no. 2
Abstract
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
