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

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..

Medienart:

Artikel

Erscheinungsjahr:

2016

Erschienen:

2016

Enthalten in:

Zur Gesamtaufnahme - volume:128

Enthalten in:

Blood - 128(2016), 11, Seite 1490

Sprache:

Englisch

Beteiligte Personen:

Vallois, David [VerfasserIn]
Dobay, Maria Pamela D [Sonstige Person]
Morin, Ryan D [Sonstige Person]
Lemonnier, François [Sonstige Person]
Missiaglia, Edoardo [Sonstige Person]
Juilland, Mélanie [Sonstige Person]
Iwaszkiewicz, Justyna [Sonstige Person]
Fataccioli, Virginie [Sonstige Person]
Bisig, Bettina [Sonstige Person]
Roberti, Annalisa [Sonstige Person]
Grewal, Jasleen [Sonstige Person]
Bruneau, Julie [Sonstige Person]
Fabiani, Bettina [Sonstige Person]
Martin, Antoine [Sonstige Person]
Bonnet, Christophe [Sonstige Person]
Michielin, Olivier [Sonstige Person]
Jais, Jean-Philippe [Sonstige Person]
Figeac, Martin [Sonstige Person]
Bernard, Olivier A [Sonstige Person]
Delorenzi, Mauro [Sonstige Person]
Haioun, Corinne [Sonstige Person]
Tournilhac, Olivier [Sonstige Person]
Thome, Margot [Sonstige Person]
Gascoyne, Randy D [Sonstige Person]
Gaulard, Philippe [Sonstige Person]
de Leval, Laurence [Sonstige Person]

Links:

Volltext
www.ncbi.nlm.nih.gov

RVK:

RVK Klassifikation

doi:

10.1182/blood-2016-02-698977

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC1985790734