La reprogrammation épigénétique induite par la stimulation chronique du TCR dévoile une nouvelle cible thérapeutique associée à la signalisation des récepteurs NK dans les lymphomes T périphériques
| العنوان: | La reprogrammation épigénétique induite par la stimulation chronique du TCR dévoile une nouvelle cible thérapeutique associée à la signalisation des récepteurs NK dans les lymphomes T périphériques |
|---|---|
| المؤلفون: | Maël Heiblig, Javeed Iqbal, Amel Chebel, Antoine Marçais, Dimitri Chartoire, Roxane M. Pommier, Philippe Gaulard, Gilles Salles, Christine Lefebvre, Emmanuel Bachy, Camille Lours, Jean Pierre Rouault, Thierry Walzer, Aurélie Verney, Pierre Sujobert, Mirjam Urb, Sunandini Sharma, Mathieu Blery, Rémy Robinot, Laurence de Leval, Sylvain Mareschal, Caroline Fezelot, Laurent Genestier, Charlotte Bertheau, Sylvain Carras, Anthony Ferrari, Lucien Courtois, Alexandra Traverse-Glehen, Edith Julia, Alyssa Bouska, David Sibon, Emilie Bardel |
| المساهمون: | Genestier, Laurent, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Activation et transduction du signal dans les lymphocytes - Lymphocyte activation and signaling (LYACTS), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Synergie Lyon Cancer [Lyon], Centre Léon Bérard [Lyon], University of Nebraska Medical Center, University of Nebraska System, Centre Hospitalier Universitaire [Grenoble] (CHU), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Lausanne = University of Lausanne (UNIL), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Innate Pharma |
| المصدر: | The Journal of clinical investigation The Journal of clinical investigation, 2021, 131 (13), pp.e139675. ⟨10.1172/jci139675⟩ The Journal of clinical investigation, vol. 131, no. 13, pp. e139675 J Clin Invest |
| بيانات النشر: | HAL CCSD, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Carcinogenesis, T cell, T-Lymphocytes, [SDV]Life Sciences [q-bio], Immunology, Receptors, Antigen, T-Cell, T cells, Syk, Hematology, Lymphomas, T cell receptor, Biology, Epigenesis, Genetic, 03 medical and health sciences, Mice, 0302 clinical medicine, medicine, Animals, Humans, Syk Kinase, Receptor, PI3K/AKT/mTOR pathway, Mice, Knockout, T-cell receptor, Lymphoma, T-Cell, Peripheral, hemic and immune systems, General Medicine, T lymphocyte, Neoplasms, Experimental, medicine.disease, Cellular Reprogramming, Genes, p53, Lymphoma, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cancer research, Receptors, Natural Killer Cell, Reprogramming, Signal Transduction, Research Article |
| الوصف: | International audience; 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1558-8238 |
| DOI: | 10.1172/jci139675⟩ |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::249c2f1c858a6406fbe8124c2abab521 https://www.hal.inserm.fr/inserm-03280949/document |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....249c2f1c858a6406fbe8124c2abab521 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15588238 |
|---|---|
| DOI: | 10.1172/jci139675⟩ |