Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.

Détails

Ressource 1Télécharger: 5_27369867_Postprint.pdf (5967.99 [Ko])
Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_A7AD3DD77F83
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
Périodique
Blood
Auteur(s)
Vallois D., Dobay M.P., Morin R.D., Lemonnier F., Missiaglia E., Juilland M., Iwaszkiewicz J., Fataccioli V., Bisig B., Roberti A., Grewal J., Bruneau J., Fabiani B., Martin A., Bonnet C., Michielin O., Jais J.P., Figeac M., Bernard O.A., Delorenzi M., Haioun C., Tournilhac O., Thome M., Gascoyne R.D., Gaulard P., de Leval L.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Statut éditorial
Publié
Date de publication
2016
Volume
128
Numéro
11
Pages
1490-1502
Langue
anglais
Résumé
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.
Pubmed
Web of science
Open Access
Oui
Création de la notice
11/11/2016 8:50
Dernière modification de la notice
20/08/2019 15:12
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