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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 p27 kip1 . 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, p27 kip1 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. T cell acute lymphoblastic leukemia IL-7 PI3K–Akt MEK–Erk Glut1 Footnotes 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. Submitted: 21 April 2004 Accepted: 30 June 2004
The Journal of Experimental Medicine – Rockefeller University Press
Published: Sep 6, 2004
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