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Fit αβ T-cell receptor suppresses leukemogenesis of Pten-deficient thymocytes.

Abstract：

: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 an αβT 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.

journal_name

Haematologica

journal_title

Haematologica

authors

Gon S,Loosveld M,Crouzet T,Potier D,Bonnet M,Morin SO,Michel G,Vey N,Nunès JA,Malissen B,Roncagalli R,Nadel B,Payet-Bornet D

doi

10.3324/haematol.2018.188359

subject

Has Abstract

pub_date

2018-06-01 00:00:00

pages

999-1007

issue

6

eissn

0390-6078

issn

1592-8721

pii

haematol.2018.188359

journal_volume

103

pub_type

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