Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming.

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State: Public
Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_C463116D7D45
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Chronic T cell receptor stimulation unmasks NK receptor signaling in peripheral T cell lymphomas via epigenetic reprogramming.
Journal
The Journal of clinical investigation
Author(s)
Carras S., Chartoire D., Mareschal S., Heiblig M., Marçais A., Robinot R., Urb M., Pommier R.M., Julia E., Chebel A., Verney A., Bertheau C., Bardel E., Fezelot C., Courtois L., Lours C., Bouska A., Sharma S., Lefebvre C., Rouault J.P., Sibon D., Ferrari A., Iqbal J., de Leval L., Gaulard P., Traverse-Glehen A., Sujobert P., Blery M., Salles G., Walzer T., Bachy E., Genestier L.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Publication state
Published
Issued date
01/07/2021
Peer-reviewed
Oui
Volume
131
Number
13
Pages
e139675
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Peripheral T cell lymphomas (PTCLs) represent a significant unmet medical need with dismal clinical outcomes. The T cell receptor (TCR) is emerging as a key driver of T lymphocyte transformation. However, the role of chronic TCR activation in lymphomagenesis and in lymphoma cell survival is still poorly understood. Using a mouse model, we report that chronic TCR stimulation drove T cell lymphomagenesis, whereas TCR signaling did not contribute to PTCL survival. The combination of kinome, transcriptome, and epigenome analyses of mouse PTCLs revealed a NK cell-like reprogramming of PTCL cells with expression of NK receptors (NKRs) and downstream signaling molecules such as Tyrobp and SYK. Activating NKRs were functional in PTCLs and dependent on SYK activity. In vivo blockade of NKR signaling prolonged mouse survival, demonstrating the addiction of PTCLs to NKRs and downstream SYK/mTOR activity for their survival. We studied a large collection of human primary samples and identified several PTCLs recapitulating the phenotype described in this model by their expression of SYK and the NKR, suggesting a similar mechanism of lymphomagenesis and establishing a rationale for clinical studies targeting such molecules.
Keywords
Hematology, Immunology, Lymphomas, T cell receptor, T cells
Pubmed
Web of science
Open Access
Yes
Create date
28/05/2021 13:13
Last modification date
31/07/2021 6:34
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