The University of Southampton
University of Southampton Institutional Repository

BRAF mutations in hairy-cell leukemia

BRAF mutations in hairy-cell leukemia
BRAF mutations in hairy-cell leukemia
Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.

Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.

Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).
2305-2315
Tiacci, Enrico
ac6f3e84-4c46-4b83-9910-c7a6e34e5ae1
Trifonov, Vladimir
3d2082e4-8dca-4d86-acd2-2c8e486f25d1
Schiavoni, Gianluca
6d3821a9-bd22-416c-8aeb-5fab1ca85840
Holmes, Antony
546faafd-2572-4ff6-8f61-9e6ab6fee920
Kern, Wolfgang
5d6f1789-addc-430c-8c5f-fe75f7fc9ca3
Martelli, Maria Paola
069b06dc-df52-4987-9bad-44c8aadeb94a
Pucciarini, Alessandra
5652a8a8-1111-4e16-9ec3-fd73a1a3c660
Bigerna, Barbara
55cae97d-d89b-4754-b7d1-d007c011965c
Pacini, Roberta
32e1a094-bc49-4b7e-b32e-d936e55b398e
Wells, Victoria A.
9d0e5f2e-9bf7-482b-b056-7045260a2bd2
Sportoletti, Paolo
27857724-1cee-4766-b7fb-dec38085d95d
Pettirossi, Valentina
6fa691fc-b11c-44a0-81cb-e9026f51a1a1
Mannucci, Roberta
d86d1d1c-5382-49f9-b775-ff214be7711d
Elliott, Oliver
7c466664-2f2b-4bd4-8aab-f4a57cb95e2c
Liso, Arcangelo
e8440070-c974-48e5-ae5d-53a642f7f81a
Ambrosetti, Achille
d843ef25-58db-4165-b85f-deb97239bcaa
Pulsoni, Alessandro
7ac8f4ba-98fe-4bbc-a6a5-babf9493bd78
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Semenzato, Gianpietro
a6d11836-d0b3-4e68-b8ed-2aba2ea18b4f
Inghirami, Giorgio
d6810adb-392a-43cd-9ed3-434bb36aa4df
Capponi, Monia
8aa50203-9b55-4fa2-8a64-474eaa9cc224
Di Raimondo, Francesco
f0e1e0fd-0281-4a3c-9fb1-abda3ce142d8
Patti, Caterina
da50bb09-f4a0-4dd7-8f83-4328c1f892b8
Arcaini, Luca
e3e9186c-2630-460f-9116-cde55ad8b625
Musto, Pellegrino
45861944-468d-4ed2-b056-453f5f179ac8
Pileri, Stefano
86c95a4e-f4a8-4b9a-900c-930693bca562
Haferlach, Claudia
0bf0896a-7b9c-451a-9e64-935ecdd7aa15
Schnittger, Susanne
5157942c-96eb-47cd-9837-3feea8ec8984
Pizzolo, Giovanni
82df788f-3730-4888-9016-76fbaee7d3b0
Foà, Robin
1e05d518-cb40-4f40-9e0e-e734caacb2e9
Farinelli, Laurent
f52b2534-d657-47bc-9589-ef2fb95dece8
Haferlach, Torsten
fff2c7bf-3212-45e3-a731-19ea532c1137
Pasqualucci, Laura
1179c741-8c20-4d4e-b9a9-503e41a8e6fe
Rabadan, Raul
4ec979bf-39e8-409f-8671-c71064faae41
Falini, Brunangelo
a074b4b4-0ee2-4905-8000-5dfbd6d8af37
Tiacci, Enrico
ac6f3e84-4c46-4b83-9910-c7a6e34e5ae1
Trifonov, Vladimir
3d2082e4-8dca-4d86-acd2-2c8e486f25d1
Schiavoni, Gianluca
6d3821a9-bd22-416c-8aeb-5fab1ca85840
Holmes, Antony
546faafd-2572-4ff6-8f61-9e6ab6fee920
Kern, Wolfgang
5d6f1789-addc-430c-8c5f-fe75f7fc9ca3
Martelli, Maria Paola
069b06dc-df52-4987-9bad-44c8aadeb94a
Pucciarini, Alessandra
5652a8a8-1111-4e16-9ec3-fd73a1a3c660
Bigerna, Barbara
55cae97d-d89b-4754-b7d1-d007c011965c
Pacini, Roberta
32e1a094-bc49-4b7e-b32e-d936e55b398e
Wells, Victoria A.
9d0e5f2e-9bf7-482b-b056-7045260a2bd2
Sportoletti, Paolo
27857724-1cee-4766-b7fb-dec38085d95d
Pettirossi, Valentina
6fa691fc-b11c-44a0-81cb-e9026f51a1a1
Mannucci, Roberta
d86d1d1c-5382-49f9-b775-ff214be7711d
Elliott, Oliver
7c466664-2f2b-4bd4-8aab-f4a57cb95e2c
Liso, Arcangelo
e8440070-c974-48e5-ae5d-53a642f7f81a
Ambrosetti, Achille
d843ef25-58db-4165-b85f-deb97239bcaa
Pulsoni, Alessandro
7ac8f4ba-98fe-4bbc-a6a5-babf9493bd78
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Trentin, Livio
457595df-2d40-4392-931c-3919eb5620ec
Semenzato, Gianpietro
a6d11836-d0b3-4e68-b8ed-2aba2ea18b4f
Inghirami, Giorgio
d6810adb-392a-43cd-9ed3-434bb36aa4df
Capponi, Monia
8aa50203-9b55-4fa2-8a64-474eaa9cc224
Di Raimondo, Francesco
f0e1e0fd-0281-4a3c-9fb1-abda3ce142d8
Patti, Caterina
da50bb09-f4a0-4dd7-8f83-4328c1f892b8
Arcaini, Luca
e3e9186c-2630-460f-9116-cde55ad8b625
Musto, Pellegrino
45861944-468d-4ed2-b056-453f5f179ac8
Pileri, Stefano
86c95a4e-f4a8-4b9a-900c-930693bca562
Haferlach, Claudia
0bf0896a-7b9c-451a-9e64-935ecdd7aa15
Schnittger, Susanne
5157942c-96eb-47cd-9837-3feea8ec8984
Pizzolo, Giovanni
82df788f-3730-4888-9016-76fbaee7d3b0
Foà, Robin
1e05d518-cb40-4f40-9e0e-e734caacb2e9
Farinelli, Laurent
f52b2534-d657-47bc-9589-ef2fb95dece8
Haferlach, Torsten
fff2c7bf-3212-45e3-a731-19ea532c1137
Pasqualucci, Laura
1179c741-8c20-4d4e-b9a9-503e41a8e6fe
Rabadan, Raul
4ec979bf-39e8-409f-8671-c71064faae41
Falini, Brunangelo
a074b4b4-0ee2-4905-8000-5dfbd6d8af37

Tiacci, Enrico, Trifonov, Vladimir, Schiavoni, Gianluca, Holmes, Antony, Kern, Wolfgang, Martelli, Maria Paola, Pucciarini, Alessandra, Bigerna, Barbara, Pacini, Roberta, Wells, Victoria A., Sportoletti, Paolo, Pettirossi, Valentina, Mannucci, Roberta, Elliott, Oliver, Liso, Arcangelo, Ambrosetti, Achille, Pulsoni, Alessandro, Forconi, Francesco, Trentin, Livio, Semenzato, Gianpietro, Inghirami, Giorgio, Capponi, Monia, Di Raimondo, Francesco, Patti, Caterina, Arcaini, Luca, Musto, Pellegrino, Pileri, Stefano, Haferlach, Claudia, Schnittger, Susanne, Pizzolo, Giovanni, Foà, Robin, Farinelli, Laurent, Haferlach, Torsten, Pasqualucci, Laura, Rabadan, Raul and Falini, Brunangelo (2011) BRAF mutations in hairy-cell leukemia. New England Journal of Medicine, 364 (24), 2305-2315. (doi:10.1056/NEJMoa1014209). (PMID:21663470)

Record type: Article

Abstract

Background: Hairy-cell leukemia (HCL) is a well-defined clinicopathological entity whose underlying genetic lesion is still obscure.

Methods: We searched for HCL-associated mutations by performing massively parallel sequencing of the whole exome of leukemic and matched normal cells purified from the peripheral blood of an index patient with HCL. Findings were validated by Sanger sequencing in 47 additional patients with HCL.

Results: Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein. Since BRAF V600E is oncogenic in other tumors, further analyses were focused on this genetic lesion. The same BRAF mutation was noted in all the other 47 patients with HCL who were evaluated by means of Sanger sequencing. None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias. In immunohistologic and Western blot studies, HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF-MEK-ERK mitogen-activated protein kinase pathway in HCL. In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK. CONCLUSIONS; The BRAF V600E mutation was present in all patients with HCL who were evaluated. This finding may have implications for the pathogenesis, diagnosis, and targeted therapy of HCL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others.).

This record has no associated files available for download.

More information

Published date: 16 June 2011
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 358123
URI: http://eprints.soton.ac.uk/id/eprint/358123
PURE UUID: cbb935f5-4f8d-42f2-900f-8a2fb374550b
ORCID for Francesco Forconi: ORCID iD orcid.org/0000-0002-2211-1831

Catalogue record

Date deposited: 08 Oct 2013 09:21
Last modified: 15 Mar 2024 03:40

Export record

Altmetrics

Contributors

Author: Enrico Tiacci
Author: Vladimir Trifonov
Author: Gianluca Schiavoni
Author: Antony Holmes
Author: Wolfgang Kern
Author: Maria Paola Martelli
Author: Alessandra Pucciarini
Author: Barbara Bigerna
Author: Roberta Pacini
Author: Victoria A. Wells
Author: Paolo Sportoletti
Author: Valentina Pettirossi
Author: Roberta Mannucci
Author: Oliver Elliott
Author: Arcangelo Liso
Author: Achille Ambrosetti
Author: Alessandro Pulsoni
Author: Livio Trentin
Author: Gianpietro Semenzato
Author: Giorgio Inghirami
Author: Monia Capponi
Author: Francesco Di Raimondo
Author: Caterina Patti
Author: Luca Arcaini
Author: Pellegrino Musto
Author: Stefano Pileri
Author: Claudia Haferlach
Author: Susanne Schnittger
Author: Giovanni Pizzolo
Author: Robin Foà
Author: Laurent Farinelli
Author: Torsten Haferlach
Author: Laura Pasqualucci
Author: Raul Rabadan
Author: Brunangelo Falini

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.

×