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Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia

PTEN (Phosphatase and TENsin homolog) is a well-known tumor suppressor involved in numerous types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). In human, loss-of-function mutations of PTEN are correlated to mature T-ALL expressing a T-cell receptor (TCR) at their cell surface. In...

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Autores principales: Pankaew, Saran, Potier, Delphine, Grosjean, Clémence, Nozais, Mathis, Quessada, Julie, Loosveld, Marie, Remy, Élisabeth, Payet-Bornet, Dominique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847596/
https://www.ncbi.nlm.nih.gov/pubmed/35185889
http://dx.doi.org/10.3389/fimmu.2022.797244
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author Pankaew, Saran
Potier, Delphine
Grosjean, Clémence
Nozais, Mathis
Quessada, Julie
Loosveld, Marie
Remy, Élisabeth
Payet-Bornet, Dominique
author_facet Pankaew, Saran
Potier, Delphine
Grosjean, Clémence
Nozais, Mathis
Quessada, Julie
Loosveld, Marie
Remy, Élisabeth
Payet-Bornet, Dominique
author_sort Pankaew, Saran
collection PubMed
description PTEN (Phosphatase and TENsin homolog) is a well-known tumor suppressor involved in numerous types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). In human, loss-of-function mutations of PTEN are correlated to mature T-ALL expressing a T-cell receptor (TCR) at their cell surface. In accordance with human T-ALL, inactivation of Pten gene in mouse thymocytes induces TCRαβ(+) T-ALL development. Herein, we explored the functional interaction between TCRαβ signaling and PTEN. First, we performed single-cell RNA sequencing (scRNAseq) of PTEN-deficient and PTEN-proficient thymocytes. Bioinformatic analysis of our scRNAseq data showed that pathological Pten(del) thymocytes express, as expected, Myc transcript, whereas inference of pathway activity revealed that these Pten(del) thymocytes display a lower calcium pathway activity score compared to their physiological counterparts. We confirmed this result using ex vivo calcium flux assay and showed that upon TCR activation tumor Pten(del) blasts were unable to release calcium ions (Ca(2+)) from the endoplasmic reticulum to the cytosol. In order to understand such phenomena, we constructed a mathematical model centered on the mechanisms controlling the calcium flux, integrating TCR signal strength and PTEN interactions. This qualitative model displays a dynamical behavior coherent with the dynamics reported in the literature, it also predicts that PTEN affects positively IP3 (inositol 1,4,5-trisphosphate) receptors (ITPR). Hence, we analyzed Itpr expression and unraveled that ITPR proteins levels are reduced in PTEN-deficient tumor cells compared to physiological and leukemic PTEN-proficient cells. However, calcium flux and ITPR proteins expression are not defective in non-leukemic PTEN-deficient T cells indicating that beyond PTEN loss an additional alteration is required. Altogether, our study shows that ITPR/Calcium flux is a part of the oncogenic landscape shaped by PTEN loss and pinpoints a putative role of PTEN in the regulation of ITPR proteins in thymocytes, which remains to be characterized.
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spelling pubmed-88475962022-02-17 Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia Pankaew, Saran Potier, Delphine Grosjean, Clémence Nozais, Mathis Quessada, Julie Loosveld, Marie Remy, Élisabeth Payet-Bornet, Dominique Front Immunol Immunology PTEN (Phosphatase and TENsin homolog) is a well-known tumor suppressor involved in numerous types of cancer, including T-cell acute lymphoblastic leukemia (T-ALL). In human, loss-of-function mutations of PTEN are correlated to mature T-ALL expressing a T-cell receptor (TCR) at their cell surface. In accordance with human T-ALL, inactivation of Pten gene in mouse thymocytes induces TCRαβ(+) T-ALL development. Herein, we explored the functional interaction between TCRαβ signaling and PTEN. First, we performed single-cell RNA sequencing (scRNAseq) of PTEN-deficient and PTEN-proficient thymocytes. Bioinformatic analysis of our scRNAseq data showed that pathological Pten(del) thymocytes express, as expected, Myc transcript, whereas inference of pathway activity revealed that these Pten(del) thymocytes display a lower calcium pathway activity score compared to their physiological counterparts. We confirmed this result using ex vivo calcium flux assay and showed that upon TCR activation tumor Pten(del) blasts were unable to release calcium ions (Ca(2+)) from the endoplasmic reticulum to the cytosol. In order to understand such phenomena, we constructed a mathematical model centered on the mechanisms controlling the calcium flux, integrating TCR signal strength and PTEN interactions. This qualitative model displays a dynamical behavior coherent with the dynamics reported in the literature, it also predicts that PTEN affects positively IP3 (inositol 1,4,5-trisphosphate) receptors (ITPR). Hence, we analyzed Itpr expression and unraveled that ITPR proteins levels are reduced in PTEN-deficient tumor cells compared to physiological and leukemic PTEN-proficient cells. However, calcium flux and ITPR proteins expression are not defective in non-leukemic PTEN-deficient T cells indicating that beyond PTEN loss an additional alteration is required. Altogether, our study shows that ITPR/Calcium flux is a part of the oncogenic landscape shaped by PTEN loss and pinpoints a putative role of PTEN in the regulation of ITPR proteins in thymocytes, which remains to be characterized. Frontiers Media S.A. 2022-02-02 /pmc/articles/PMC8847596/ /pubmed/35185889 http://dx.doi.org/10.3389/fimmu.2022.797244 Text en Copyright © 2022 Pankaew, Potier, Grosjean, Nozais, Quessada, Loosveld, Remy and Payet-Bornet https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pankaew, Saran
Potier, Delphine
Grosjean, Clémence
Nozais, Mathis
Quessada, Julie
Loosveld, Marie
Remy, Élisabeth
Payet-Bornet, Dominique
Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title_full Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title_fullStr Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title_full_unstemmed Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title_short Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia
title_sort calcium signaling is impaired in pten-deficient t cell acute lymphoblastic leukemia
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847596/
https://www.ncbi.nlm.nih.gov/pubmed/35185889
http://dx.doi.org/10.3389/fimmu.2022.797244
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