Journal
HAEMATOLOGICA
Volume 103, Issue 6, Pages 999-1007Publisher
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2018.188359
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Funding
- LYSARC-Institut CARNOT CALYM-ANR [R14-2014, R20-2015, R29-2016, R31-2017]
- CNRS
- INSERM
- Canceropole PACA
- la Fondation pour la Recherche Medicale [ING20121226364]
- INCa [ASC12035ASA]
- Aix-Marseille Universite
- Fondation pour la Recherche Medicale [Equipe FRM DEQ20140329534]
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Signaling through the alpha beta T cell receptor (TCR) is a crucial determinant of T-cell fate and can induce two opposite outcomes during thymocyte development: cell death or survival and differentiation. To date, the role played by T-cell receptor in the oncogenic transformation of developing T cells remains unclear. Here we show that human primary T-cell acute lymphoblastic leukemias expressing an alpha beta T cell receptor are frequently deficient for phosphatase and tensin homolog protein (PTEN), and fail to respond strongly to T-cell receptor activation. Using Pten-deficient T-cell acute lymphoblastic leukemia mouse models, we confirm that T-cell receptor signaling is involved in leukemogenesis. We show that abrogation of T-cell receptor expression accelerated tumor onset, while enforced expression of a fit transgenic T-cell receptor led to the development of T-cell receptor-negative lymphoma and delayed tumorigenesis. We further demonstrate that pre-tumoral Pten-deficient thymocytes harboring fit T-cell receptors undergo early clonal deletion, thus preventing their malignant transformation, while cells with unfit T-cell receptors that should normally be deleted during positive selection, pass selection and develop T-cell acute lymphoblastic leukemias. Altogether, our data show that fit T-cell receptor signaling suppresses tumor development mediated by Pten loss-of-function and point towards a role of Pten in positive selection.
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