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

Saran Pankaew (1, 2) , Delphine Potier (2) , Clémence Grosjean (2) , Mathis Nozais (2) , Julie Quessada (2, 3) , Marie Loosveld (2, 3) , Dominique Payet-Bornet (2) , Élisabeth Remy (1)

1 I2M - Institut de Mathématiques de Marseille
2 CIML - Centre d'Immunologie de Marseille - Luminy
3 Laboratoire d'hématologie biologique [Hôpital de la Timone - Hôpital Nord - APHM]

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.

Mots clés: thymocytes; T-ALL; PTEN; TCR signaling; calcium signaling; single-cell RNA-seq; qualitative mathematical model

Domaines: Sciences du Vivant [q-bio]; Mathématiques [math]

Saran Pankaew, Delphine Potier, Clémence Grosjean, Mathis Nozais, Julie Quessada, et al.. Calcium Signaling Is Impaired in PTEN-Deficient T Cell Acute Lymphoblastic Leukemia. Frontiers in Immunology, 2022, 13, ⟨10.3389/fimmu.2022.797244⟩. ⟨hal-03555080⟩