The role of sphingosine kinase in IL-7-mediated signaling ant T-cell acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most common malignancy in pediatric patients and is characterized by bone marrow and peripheral blood invasion from malignant lymphoblasts. Approximately 15% of children and 25% of adult ALL cases are of T-cell phenotype (T-ALL), which is associated with high risk and poorer prognosis. Interleukin-7 (IL-7) and its receptor (IL-7R) are essential for normal T-cell development and homeostasis. However, IL-7/IL-7R-mediated signaling may also partake in leukemia development, as demonstrated by the identification of IL-7Rα gainof- function mutations in around 9% of T-ALL patients. Sphingosine Kinase (SPHK) is a lipid kinase that promotes cell viability by phosphorylating sphingosine and thereby regulating the ceramide/sphingosine 1- phosphate (S1P) rheostat. Cancer cells frequently display high levels of SPHK, and SPHK expression has been correlated with cancer patients’ outcome. Previous studies have shown that increased SPHK levels are correlated with increased cell viability and inhibition of apoptosis in chronic myeloid leukemia and acute myeloid leukemia. Here, we show that SPHK is an important player in IL-7-mediated signaling in TALL. Initially, we demonstrated that SPHK1 expression was increased in T-ALL cells compared to its normal counterparts. We then hypothesized that SPHK1 could be involved in IL-7-mediated positive effects in T-ALL cells (both IL-7-dependent and IL- 7Rα mutant), as well as in normal T-cells. We demonstrated that IL-7 activates SPHK activity without significantly impacting on its expression. SPHK inhibition completely prevented IL-7-mediated activation of PI3K/AKT and STAT5 pathways, suggesting that SPHK activity is fundamental for the activation of IL-7-dependent survival pathways. In accordance, inhibition of SPHK decreased IL-7-dependent maintenance of mitochondrial membrane potential and cell viability. In addition, SPHK was necessary for IL-7-dependent cell cycle progression, with its inhibition inducing an arrest in G0/G1. Finally, SPHK inhibition downregulated CD71 surface expression and cell size in T-ALL. In summary, our study identifies SPHK1 as an essential modulator of IL-7- mediated signaling in T-ALL, and opens new possible therapeutic approaches by using SPHK pharmacological inhibitors in the treatment of T-ALL patients.