Publication: Fit αβ T-Cell Receptor suppresses leukemogenesis of Pten-deficient thymocytes.

Published in: Haematologica, 2018, ⟨10.3324/haematol.2018.188359⟩

Authors: Stéphanie Gon, Marie Loosveld, Thomas Crouzet, Delphine Potier, Mélanie Bonnet, Stéphanie Morin, Gérard Michel, Norbert Vey, Jacques Nunes, Bernard Malissen, Romain Roncagalli, Bertrand Nadel, Dominique Payet-Bornet

Summary

Signaling through the αβT 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 a αβT cell receptor are frequently deficient for phosphatase and tensin homolog protein (PTEN), and fail to strongly respond 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 pinpoint to a role of Pten in positive selection.

Link to Pubmed [PMID] – 29567770

Link to HAL – hal-01772992

Link to DOI – 10.3324/haematol.2018.188359