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Acute Lymphoblastic Leukemia
Fit αβ T-cell receptor suppresses leukemogenesis of Pten-deficient thymocytes
Stéphanie Gon,1* Marie Loosveld,1,2* Thomas Crouzet,1 Delphine Potier,1 Mélanie Bonnet,1 Stéphanie O. Morin,3 Gérard Michel,4 Norbert Vey,3,5 Jacques A. Nunès,3 Bernard Malissen,1 Romain Roncagalli,1 Bertrand Nadel,1 and Dominique Payet-Bornet1
1Aix-Marseille Université, CNRS, INSERM, CIML; 2APHM, Hôpital La Timone, Laboratoire d’Hématologie; 3Aix-Marseille Université, CNRS, INSERM, Institut Paoli-Calmettes, CRCM; 4APHM, Hôpital La Timone, Service d’Hématologie et d’Oncologie Pédiatrique and 5Institut Paoli-Calmettes, Hematology Department, Marseille, France
*These authors contributed equally to this work.
ABSTRACT
Signaling through the αβT cell receptor (TCR) is a crucial determi- nant 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 transforma- tion 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.
Introduction
Thymopoiesis aims to create a repertoire of mature T cells equipped with a diverse array of functional αβ or δg T-cell receptors (TCR) able to recognize the broadest possible range of foreign antigens. This large receptor diversity is mainly due to the V(D)J recombination process, in which few of a large pool of V, D and J gene segments are somatically rearranged with imprecise joining. The price to pay for this strategy of random generation of diversity is the creation of a high load of CD4+ CD8+ DP cortical thymocytes bearing no, or “unfit” receptors, i.e. displaying a too low or too high affinity for self peptide-major histocompatibility complex (p- MHC), and which will have to be eliminated through death by neglect (>90% thy- mocytes) and negative selection (Online Supplementary Figure S1A).1 Only the small pool of thymocytes expressing TCR with intermediate affinity and/or avidity for p- MHC (denoted here as fit TCR) will be induced to further differentiate into mature CD4 or CD8 single-positive (SP) thymocytes, a transition known as positive selec- tion. Therefore, TCR signaling can induce two opposite outcomes during thymo- cyte development: cell death or survival and differentiation.
Somatic rearrangement, proliferation and selection provide a propitious environ- ment for major derailments of thymocyte ontogeny. T-cell acute lymphoblastic leukemias (T-ALL) are malignant proliferation of such T-cell progenitors abnormally arrested at various stages of their maturation process (Online Supplementary Figure S1B).2-4 They constitute a particularly heterogeneous group of diseases, resulting
Ferrata Storti Foundation
Haematologica 2018 Volume 103(6):999-1007
Correspondence:
payet@ciml.univ-mrs.fr/nadel@ciml.univ-mrs.fr
Received: January 11, 2018. Accepted: March 15, 2018. Pre-published: March 22, 2018.
doi:10.3324/haematol.2018.188359
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/999
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