The Journal of Experimental Medicine
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Published 7 September 2004. doi:10.1084/jem.20040789
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 5, 659-669
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Activation of PI3K Is Indispensable for Interleukin 7–mediated Viability, Proliferation, Glucose Use, and Growth of T Cell Acute Lymphoblastic Leukemia Cells

Joao T. Barata1, Ana Silva1, Joana G. Brandao1, Lee M. Nadler2, Angelo A. Cardoso2, and Vassiliki A. Boussiotis2

1 Tumor Biology Unit, Institute of Molecular Medicine, University of Lisbon Medical School, 1649-028, Lisbon, Portugal
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115

Address correspondence to Vassiliki A. Boussiotis, Dana-Farber Cancer Institute, 44 Binney St., Room Mayer 547, Boston, MA 02115. Phone: (617) 632-4586; Fax: (617) 632-5167; email: vassiliki_boussiotis{at}dfci.harvard.edu

Interleukin (IL)-7 is essential for normal T cell development. Previously, we have shown that IL-7 increases viability and proliferation of T cell acute lymphoblastic leukemia (T-ALL) cells by up-regulating Bcl-2 and down-regulating the cyclin-dependent kinase inhibitor p27kip1. Here, we examined the signaling pathways via which IL-7 mediates these effects. We investigated mitogen-activated protein kinase (MEK)–extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)–Akt (protein kinase B) pathways, which have active roles in T cell expansion and have been implicated in tumorigenesis. IL-7 induced activation of the MEK–Erk pathway in T-ALL cells; however, inhibition of the MEK–Erk pathway by the use of the cell-permeable inhibitor PD98059, did not affect IL-7–mediated viability or cell cycle progression of leukemic cells. IL-7 induced PI3K-dependent phosphorylation of Akt and its downstream targets GSK-3, FOXO1, and FOXO3a. PI3K activation was mandatory for IL-7–mediated Bcl-2 up-regulation, p27kip1 down-regulation, Rb hyperphosphorylation, and consequent viability and cell cycle progression of T-ALL cells. PI3K signaling was also required for cell size increase, up-regulation of CD71, expression of the glucose transporter Glut1, uptake of glucose, and maintenance of mitochondrial integrity. Our results implicate PI3K as a major effector of IL-7–induced viability, metabolic activation, growth and proliferation of T-ALL cells, and suggest that PI3K and its downstream effectors may represent molecular targets for therapeutic intervention in T-ALL.

Key Words: T cell acute lymphoblastic leukemia • IL-7 • PI3K–Akt • MEK–Erk • Glut1

A.A. Cardoso and V.A. Boussiotis contributed equally to the supervision of this work.

Abbreviations used in this paper: cdk, cyclin-dependent kinase; Erk, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase; MIF, mean intensity of fluorescence; PI3K, phosphatidylinositol-3-kinase; T-ALL, T cell acute lymphoblastic leukemia.


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