The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

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. 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.

0390-6078
448-456
Diop, Fary
7a226151-8451-4a71-9ecc-0014d1aef5da
Moia, Riccardo
238132cf-c6b3-4ea3-b647-9932397edd63
Favini, Chiara
9336b5c7-218a-495d-9858-1a34d9e7bcc4
Spaccarotella, Elisa
56d86698-b869-41a6-814f-b97c508f014a
De Paoli, Lorenzo
9390755d-1a39-47e9-bc54-69f9fe914248
Bruscaggin, Alessio
0a5ac2c3-9c5d-489c-8e5f-bb108166da61
Spina, Valeria
bb72602d-3d56-424f-b169-47377aef1d10
Terzi-di-Bergamo, Lodovico
559ca9b8-cb00-48c1-baa1-d23867bcde93
Arruga, Francesca
9104b822-4467-4ed7-b914-2dd830beb917
Tarantelli, Chiara
c68ceac4-3a9b-4f13-8ceb-7c1352a2c821
Deambrogi, Clara
c7d10651-681c-41b9-97b6-bf68f3c1243d
Rasi, Silvia
13639ced-c17f-4350-87e4-fb670cee592b
Adhinaveni, Ramesh
944b325d-eb3e-4e0e-8df9-4ba14cfb4245
Patriarca, Andrea
266f89da-0a91-4d5e-8308-ecdd729e081f
Favini, Simone
646c8677-f025-403f-af50-a52c7da6f342
Sagiraju, Sruthi
235a65db-ff4e-4f7d-8883-2dc1258c367b
Jabangwe, Clive
6de0be73-c3a8-45b1-8d1d-a3dec0f45784
Kodipad, Ahad A.
ed443063-2dcf-42fe-824e-e0df35c95393
Peroni, Denise
bc0d13fe-a555-41fe-88b3-74c07303be16
Mauro, Francesca R.
598dfb32-f6c8-4a1a-bcf9-46db14ff6996
Del Giudice, Ilaria
a795b784-a413-486a-929b-9143125d26a6
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Cortelezzi, Agostino
74e1d495-be0e-4b32-8c36-64a3772414e8
Zaja, Francesco
d452d03a-c851-4bcc-ab06-4ac8e7fb348e
Bomben, Riccardo
2de7f588-50b7-43f6-8bb9-ec0a0896b8e5
Rossi, Francesca Maria
c5190191-d4a9-494f-9c84-9bce7feb46a5
Visco, Carlo
2c102cee-f0d7-4738-9cd9-ca366c735c1b
Chiarenza, Annalisa
4a8cf2ac-1cdc-436e-a8ac-62f713bcb678
Rigolin, Gian Matteo
5958cdec-182f-46fb-a56c-58754f4e1aea
Marasca, Roberto
918148d0-8f99-4a29-8322-1b34f6d7dd00
Coscia, Marta
7ae299af-adc7-41fd-aa4b-b3ee6fe91d83
Perbellini, Omar
c6866d34-4fa3-48b0-af89-ab8af0bb3a33
Tedeschi, Alessandra
476ff202-6261-4efe-86ec-e1c3c60a7449
Laurenti, Luca
23c6052d-80af-4fac-92da-2a495a8cb440
Motta, Marina
023df833-fe23-4c2a-baef-5154f8fd3d79
Donaldson, David
7f9999fd-a66a-4b37-8896-cad4843d25cb
Weir, Phil
51137e33-85f9-4eef-81d3-cb674b1b1613
Mills, Ken
d9e5594b-88de-480b-bc15-15b6bbe94a92
Thornton, Patrick
117fcb39-72d8-4453-b315-af643790c6a1
Lawless, Sarah
fe11b444-820b-4ea9-8b82-31769b5299d2
Bertoni, Francesco
13297a2f-854a-4841-a410-d6bfca8afee8
Del Poeta, Giovanni
ed2857f8-ebfc-4d88-96cd-21423e57738d
Cuneo, Antonio
d88ead48-2932-48f0-82c3-85dbe57d7d63
Follenzi, Antonia
1f561120-67f8-4f33-b208-eaae821980cb
Gattei, Valter
df828ae8-1b40-4acb-8908-5a6b3d16cf99
Boldorini, Renzo Luciano
6d73d26a-bf5d-4584-bc66-e19020b6e733
Catherwood, Mark
71ac2089-8005-42c5-a385-fa9c209647f2
Deaglio, Silvia
2e20f72c-3eb1-4388-a371-8cace561211c
Foá, Robin
28cfade0-287d-467e-8882-4d9467b62e5a
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a
Rossi, Davide
b4b2506d-794c-4c79-8b2d-6767554fd52a
Diop, Fary
7a226151-8451-4a71-9ecc-0014d1aef5da
Moia, Riccardo
238132cf-c6b3-4ea3-b647-9932397edd63
Favini, Chiara
9336b5c7-218a-495d-9858-1a34d9e7bcc4
Spaccarotella, Elisa
56d86698-b869-41a6-814f-b97c508f014a
De Paoli, Lorenzo
9390755d-1a39-47e9-bc54-69f9fe914248
Bruscaggin, Alessio
0a5ac2c3-9c5d-489c-8e5f-bb108166da61
Spina, Valeria
bb72602d-3d56-424f-b169-47377aef1d10
Terzi-di-Bergamo, Lodovico
559ca9b8-cb00-48c1-baa1-d23867bcde93
Arruga, Francesca
9104b822-4467-4ed7-b914-2dd830beb917
Tarantelli, Chiara
c68ceac4-3a9b-4f13-8ceb-7c1352a2c821
Deambrogi, Clara
c7d10651-681c-41b9-97b6-bf68f3c1243d
Rasi, Silvia
13639ced-c17f-4350-87e4-fb670cee592b
Adhinaveni, Ramesh
944b325d-eb3e-4e0e-8df9-4ba14cfb4245
Patriarca, Andrea
266f89da-0a91-4d5e-8308-ecdd729e081f
Favini, Simone
646c8677-f025-403f-af50-a52c7da6f342
Sagiraju, Sruthi
235a65db-ff4e-4f7d-8883-2dc1258c367b
Jabangwe, Clive
6de0be73-c3a8-45b1-8d1d-a3dec0f45784
Kodipad, Ahad A.
ed443063-2dcf-42fe-824e-e0df35c95393
Peroni, Denise
bc0d13fe-a555-41fe-88b3-74c07303be16
Mauro, Francesca R.
598dfb32-f6c8-4a1a-bcf9-46db14ff6996
Del Giudice, Ilaria
a795b784-a413-486a-929b-9143125d26a6
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Cortelezzi, Agostino
74e1d495-be0e-4b32-8c36-64a3772414e8
Zaja, Francesco
d452d03a-c851-4bcc-ab06-4ac8e7fb348e
Bomben, Riccardo
2de7f588-50b7-43f6-8bb9-ec0a0896b8e5
Rossi, Francesca Maria
c5190191-d4a9-494f-9c84-9bce7feb46a5
Visco, Carlo
2c102cee-f0d7-4738-9cd9-ca366c735c1b
Chiarenza, Annalisa
4a8cf2ac-1cdc-436e-a8ac-62f713bcb678
Rigolin, Gian Matteo
5958cdec-182f-46fb-a56c-58754f4e1aea
Marasca, Roberto
918148d0-8f99-4a29-8322-1b34f6d7dd00
Coscia, Marta
7ae299af-adc7-41fd-aa4b-b3ee6fe91d83
Perbellini, Omar
c6866d34-4fa3-48b0-af89-ab8af0bb3a33
Tedeschi, Alessandra
476ff202-6261-4efe-86ec-e1c3c60a7449
Laurenti, Luca
23c6052d-80af-4fac-92da-2a495a8cb440
Motta, Marina
023df833-fe23-4c2a-baef-5154f8fd3d79
Donaldson, David
7f9999fd-a66a-4b37-8896-cad4843d25cb
Weir, Phil
51137e33-85f9-4eef-81d3-cb674b1b1613
Mills, Ken
d9e5594b-88de-480b-bc15-15b6bbe94a92
Thornton, Patrick
117fcb39-72d8-4453-b315-af643790c6a1
Lawless, Sarah
fe11b444-820b-4ea9-8b82-31769b5299d2
Bertoni, Francesco
13297a2f-854a-4841-a410-d6bfca8afee8
Del Poeta, Giovanni
ed2857f8-ebfc-4d88-96cd-21423e57738d
Cuneo, Antonio
d88ead48-2932-48f0-82c3-85dbe57d7d63
Follenzi, Antonia
1f561120-67f8-4f33-b208-eaae821980cb
Gattei, Valter
df828ae8-1b40-4acb-8908-5a6b3d16cf99
Boldorini, Renzo Luciano
6d73d26a-bf5d-4584-bc66-e19020b6e733
Catherwood, Mark
71ac2089-8005-42c5-a385-fa9c209647f2
Deaglio, Silvia
2e20f72c-3eb1-4388-a371-8cace561211c
Foá, Robin
28cfade0-287d-467e-8882-4d9467b62e5a
Gaidano, Gianluca
1a6a7107-107b-4891-82e0-5fedadd2f65a
Rossi, Davide
b4b2506d-794c-4c79-8b2d-6767554fd52a

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. 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.

Text
haematol.2019.219550.full - Accepted Manuscript
Download (1MB)

More information

Accepted/In Press date: 24 July 2019
e-pub ahead of print date: 1 August 2019
Published date: February 2020

Identifiers

Local EPrints ID: 434863
URI: http://eprints.soton.ac.uk/id/eprint/434863
ISSN: 0390-6078
PURE UUID: d91d2c9d-99b6-4656-8229-921deffc3263

Catalogue record

Date deposited: 11 Oct 2019 16:30
Last modified: 25 Nov 2021 21:25

Export record

Altmetrics

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: 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

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×