Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

作者：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 Ahmed Kodipad, Denise Peroni, Francesca Romana Mauro, Ilaria Del Giudice, Francesco Forconi, Agostino Cortelezzi, Francesco F. 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 Ian Donaldson, Philip Weir, Ken Mills, Patrick D. Thornton, Sarah Lawless, Francesco Bertoni, Giovanni Del Poeta, Antonio Cuneo, Antonia Follenzi, Valter Gattei, Renzo Luciano Boldorini, Mark Alexander Catherwood, Silvia Deaglio, Robin Foà, Gianluca Gaïdano, Davide Rossi · 发表于：Haematologica · 年份：2019 · DOI：10.3324/haematol.2019.219550 · 被引用次数：90 · 研究领域：Chronic Lymphocytic Leukemia Research、Immunodeficiency and Autoimmune Disorders、Cell death mechanisms and regulation

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