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Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia

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-êB 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 fludarabine. In order to confirm in patients that BIRC3mutations 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 BIRC3mutations 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.

0390-6078
448-456
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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, Foá, Robin, Gaidano, Gianluca and Rossi, Davide (2020) Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia. Haematologica, 105 (2), 448-456. (doi:10.3324/haematol.2019.219550).

Record type: Article

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-êB 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 fludarabine. In order to confirm in patients that BIRC3mutations 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 BIRC3mutations 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.

Text
haematol.2019.219550.full - Accepted Manuscript
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Accepted/In Press date: 24 July 2019
e-pub ahead of print date: 1 August 2019
Published date: February 2020
Additional Information: Funding Information: This work was supported by: Molecular bases of disease dissemination in lymphoid malignancies to optimize curative therapeutic strategies, (5 x 1000 n. 21198), Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy (grants to GG and RF) and Progetti di Rilevante Interesse Nazionale (PRIN), (2015ZMRFEA), Rome, Italy; partially funded by the AGING Project – Department of Excellence – DIMET, Università del Piemonte Orientale, Novara, Italy; partially funded by Novara AIL ONLUS, Novara, Italy; Associazione Italiana per la Ricerca sul Cancro (AIRC IG-17314); Swiss Cancer League, ID HSR-4660-11-2018, Bern, Switzerland; Research Advisory Board of the Ente Ospedaliero Cantonale, Bellinzona, Switzerland; European Research Council (ERC) Consolidator grant CLL-CLONE ID: 772051; grant n. 320030_169670/1 Swiss National Science Foundation, Berne, Switzerland; Fondazione Fidinam, Lugano, Switzerland; Nelia & Amadeo Barletta Foundation, Lausanne, Switzerland; Fond’Action, Lausanne, Switzerland; Translational Research Program, grant n. 6594-20, The Leukemia & Lymphoma Society, New York, USA. Publisher Copyright: © 2020 Ferrata Storti Foundation.
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Identifiers

Local EPrints ID: 434863
URI: http://eprints.soton.ac.uk/id/eprint/434863
DOI: doi:10.3324/haematol.2019.219550
ISSN: 0390-6078
PURE UUID: d91d2c9d-99b6-4656-8229-921deffc3263
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

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Date deposited: 11 Oct 2019 16:30
Last modified: 16 Mar 2024 04:09

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Contributors

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

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