Biological and clinical implications of <i>BIRC3</i> mutations in chronic lymphocytic leukemia

Fary Diop(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Riccardo Moia(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Chiara Favini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Elisa Spaccarotella(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Lorenzo De Paoli(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Alessio Bruscaggin(Institute of Oncology Research), Valeria Spina(Institute of Oncology Research), Lodovico Terzi-di-Bergamo(Institute of Oncology Research), Francesca Arruga(Italian institute for Genomic Medicine), Chiara Tarantelli(Institute of Oncology Research), Clara Deambrogi(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Silvia Rasi(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Ramesh Adhinaveni(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Andrea Patriarca(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Simone Favini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Sruthi Sagiraju(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Clive Jabangwe(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Ahad Ahmed Kodipad(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Denise Peroni(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Francesca Romana Mauro(Sapienza University of Rome), Ilaria Del Giudice(Sapienza University of Rome), Francesco Forconi(University of Siena), Agostino Cortelezzi(University of Milan), Francesco Zaja(University of Udine), Riccardo Bomben(Centro di Riferimento Oncologico), Francesca Maria Rossi(Centro di Riferimento Oncologico), Carlo Visco(Ospedale San Bortolo), Annalisa Chiarenza(Policlinico Universitario di Catania), Gian Matteo Rigolin(University of Ferrara), Roberto Marasca(University of Modena and Reggio Emilia), Marta Coscia(Azienda Ospedaliera Citta' della Salute e della Scienza di Torino), Omar Perbellini(University of Verona), Alessandra Tedeschi(Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda), Luca Laurenti(Agostino Gemelli University Polyclinic), Marina Motta(Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia), D. Donaldson(Belfast Health and Social Care Trust), Philip Weir(Belfast Health and Social Care Trust), Ken Mills(Queen's University Belfast), Patrick Thornton(Beaumont Hospital), Sarah Lawless(Belfast Health and Social Care Trust), Francesco Bertoni(Institute of Oncology Research), Giovanni Del Poeta(University of Rome Tor Vergata), Antonio Cuneo(University of Ferrara), Antonia Follenzi(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Valter Gattei(Centro di Riferimento Oncologico), Renzo Boldorini(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Mark Catherwood(Belfast Health and Social Care Trust), Silvia Deaglio(Italian institute for Genomic Medicine), Robin Foà(Sapienza University of Rome), Gianluca Gaïdano(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Davide Rossi(Institute of Oncology Research)
Haematologica
August 1, 2019
10.3324/haematol.2019.219550
Cited by 84Open Access
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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

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