Page 214 - 2020_02-Haematologica-web

Chronic Lymphocytic Leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):448-456
Biological and clinical implications of BIRC3 mutations in chronic lymphocytic leukemia
Fary Diop,1* Riccardo Moia,1* Chiara Favini,1 Elisa Spaccarotella,1 Lorenzo De Paoli,1 Alessio Bruscaggin,2 Valeria Spina,2 Lodovico Terzi-di-Bergamo,2 Francesca Arruga,3 Chiara Tarantelli,4 Clara Deambrogi,1 Silvia Rasi,1 Ramesh Adhinaveni,1 Andrea Patriarca,1 Simone Favini,1 Sruthi Sagiraju,1 Clive Jabangwe,1 Ahad A. Kodipad,1 Denise Peroni,1 Francesca R. Mauro,5 Ilaria Del Giudice,5 Francesco Forconi,6,7 Agostino Cortelezzi,8 Francesco Zaja,9 Riccardo Bomben,10 Francesca Maria Rossi,10 Carlo Visco,11 Annalisa Chiarenza,12 Gian Matteo Rigolin,13 Roberto Marasca,14 Marta Coscia,15 Omar Perbellini,16 Alessandra Tedeschi,17 Luca Laurenti,18 Marina Motta,19 David Donaldson,20 Phil Weir,20 Ken Mills,21 Patrick Thornton,22 Sarah Lawless,20 Francesco Bertoni,4 Giovanni Del Poeta,23 Antonio Cuneo,13 Antonia Follenzi,24 Valter Gattei,10 Renzo Luciano Boldorini,25 Mark Catherwood,20 Silvia Deaglio,3 Robin Foà,5 Gianluca Gaidano1° and Davide Rossi2°
1Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; 2Institute of Oncology Research and Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; 3Department of Medical Sciences, University of Turin & Italian Institute for Genomic Medicine, Turin, Italy; 4Università della Svizzera Italiana, Institute of Oncology Research, Bellinzona, Switzerland; 5Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy; 6Cancer Sciences Unit, Southampton Cancer Research UK and National Institute for Health Research Experimental Cancer Medicine Centre, University of Southampton, Southampton, UK; 7Division of Hematology, University of Siena, Siena, Italy; 8Department of Hematology Oncology, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico and University of Milan, Milan, Italy; 9Clinica Ematologica, DAME, University of Udine, Udine, Italy; 10Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Aviano, Italy; 11Department of Cell Therapy and Hematology, Ospedale San Bortolo, Vicenza, Italy; 12Division of Hematology, Azienda Ospedaliera Universitaria Policlinico-OVE, Catania, Italy; 13Hematology Section, Azienda Ospedaliero Universitaria Arcispedale S. Anna, University of Ferrara, Ferrara, Italy; 14Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy; 15Division of Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza and University of Turin, Turin, Italy; 16Section of Hematology, Department of Medicine, University of Verona, Verona, Italy; 17Department of Oncology/Haematology, Niguarda Cancer Center, Niguarda Ca Granda Hospital, Milan, Italy; 18Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; 19Department of Hematology, Spedali Civili, Brescia, Italy; 20Clinical Haematology, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK; 21Centre for Cancer Research and Cell Biology (CCRCB), Queen’s University Belfast, Belfast, Northern Ireland, UK; 22Department of Haematology, Beaumont Hospital, Dublin, Ireland; 23Department of Hematology, Tor Vergata University, Rome, Italy; 24Department of Health Sciences, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy; 25Department of Pathology, University of Eastern Piedmont Amedeo Avogadro, Novara, Italy.
**FD and RM contributed equally to this work °GG and DR contributed equally to this work.
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 docu- mented 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 resist- ance to fludarabine-based chemoimmunotherapy, a retrospective multicen- ter cohort of 287 untreated patients receiving first-line FCR was analyzed
Correspondence:
DAVIDE ROSSI
davide.rossi@eoc.ch
GIANLUCA GAIDANO
gianluca.gaidano@med.uniupo.it
Received: March 29, 2019. Accepted: July 24, 2019. Pre-published: August 1, 2019.
doi:10.3324/haematol.2019.219550
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/448
©2020 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
448
haematologica | 2020; 105(2)
ARTICLE