Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Luca Laurenti, Alessandra Tedeschi, Robin Foa, 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 JabangweAhad 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, 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, Gianluca Gaidano, Davide Rossi

Risultato della ricerca: Contributo in rivistaArticolo in rivista

19 Citazioni (Scopus)

Abstract

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Also, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first line fludarabine, cyclophosphamide, and rituximab (FCR). Immunoblotting analysis showed that the non-canonical NF-kB pathway is active in BIRC3 mutated cell lines and 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 fludarabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated CLL receiving first-line FCR was analyzed by targeted next generation sequencing (NGS) of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a very poor prognostic subgroup of patients failing FCR [(median progression free survival (PFS): 2.2 years, p < 0.001] similar to cases harboring TP53 mutations (median PFS: 2.6 years, p < 0.0001]. BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio (HR) of 2.8 (95% C.I. 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.
Lingua originaleEnglish
pagine (da-a)N/A-N/A
RivistaHaematologica
DOI
Stato di pubblicazionePubblicato - 2019

Keywords

  • Chronic Lymphocytic Leukemia
  • Cytogenetics and Molecular Genetics
  • Molecular predictors

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