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

作者：Vallois, David; Dobay, Maria Pamela D.; Morin, Ryan D.; Lemonnier, Francois; Missiaglia, Edoardo; Juilland, Melanie; Iwaszkiewicz, Justyna; Fataccioli, Virginie; Bisig, Bettina; Roberti, Annalisa; Grewal, Jasleen; Bruneau, Julie; Fabiani, Bettina; Martin, Antoine; Bonnet, Christophe; Michielin, Olivier; Jais, Jean-Philippe; Figeac, Martin; Bernard, Olivier A.; Delorenzi, Mauro; Haioun, Corinne; Tournilhac, Olivier; Thome, Margot; Gascoyne, Randy D.; Gaulard, Philippe

来源：Blood, 2016, 128(11): 1490-1502.

DOI：10.1182/blood-2016-02-698977

• STAT3 MUTATIONS
• SEZARY-SYNDROME
• PROLYMPHOCYTIC LEUKEMIA
• RECURRENT MUTATIONS
• MISSENSE MUTATION
• NK CELLS
• KINASE
• RHOA
• EXPRESSION
• LANDSCAPE

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-kappa B 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.

• 出版日期2016-9-15