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

Details

Ressource 1Download: 5_27369867_Postprint.pdf (5967.99 [Ko])
State: Public
Version: Author's accepted manuscript
Serval ID
serval:BIB_A7AD3DD77F83
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
Journal
Blood
Author(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
Publication state
Published
Issued date
2016
Volume
128
Number
11
Pages
1490-1502
Language
english
Abstract
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
Yes
Create date
11/11/2016 8:50
Last modification date
20/08/2019 15:12
Usage data