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Acute Leukemias

Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells

Leukemia volume 25, pages 960–967 (2011)Cite this article

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Abstract

Interleukin-7 (IL-7) activates phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, thereby mediating viability, proliferation and growth of T-cell acute lymphoblastic leukemia (T-ALL) cells. Reactive oxygen species (ROS) can be upregulated by growth factors and are known to regulate proliferation and viability. Here, we show that IL-7 upregulates ROS in T-ALL cells in a manner that is dependent on PI3K/Akt/mTOR pathway activity and that relies on both NADPH oxidase and mitochondrial respiratory chain. Conversely, IL-7-induced activation of PI3K signaling pathway requires mitochondrial respiration and ROS. We have previously shown that IL-7-mediated activation of PI3K pathway drives the upregulation of the glucose transporter Glut1, promoting glucose uptake in T-ALL cells. Using phloretin to inhibit Glut function, we demonstrate that glucose uptake is mandatory for ROS upregulation in IL-7-treated T-ALL cells, suggesting that IL-7 stimulation leads to increased ROS via PI3K pathway activation and consequent upregulation of Glut1 and glucose uptake. Overall, our data reveal the existence of a critical crosstalk between PI3K/Akt signaling pathway and ROS that is essential for IL-7-mediated T-ALL cell survival, and that may constitute a novel target for therapeutic intervention.

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Acknowledgements

We thank the contribution of patients and their families, and Dr Mário Chagas and all the physicians and nurses at the Pediatric Service of Instituto Português de Oncologia de Lisboa, in generously providing primary samples. This work was supported by grants from Associação Portuguesa Contra a Leucemia, and Fundação para a Ciência e a Tecnologia-FCT (PTDC/SAU-OBD/104816). AS and AG had PhD and postdoc fellowships from FCT, respectively.

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Authors and Affiliations

  1. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

    A Silva, A Gírio, I Cebola, C I Santos & J T Barata

  2. Departamento e Centro de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal

    F Antunes

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  1. A Silva
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Correspondence to J T Barata.

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Silva, A., Gírio, A., Cebola, I. et al. Intracellular reactive oxygen species are essential for PI3K/Akt/mTOR-dependent IL-7-mediated viability of T-cell acute lymphoblastic leukemia cells. Leukemia 25, 960–967 (2011). https://doi.org/10.1038/leu.2011.56

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