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Blood, 1 March 2006, Vol. 107, No. 5, pp. 1847-1856.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-04-1612.
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HEMATOPOIESIS
G-CSF induced reactive oxygen species involves Lyn-PI3-kinase-Akt and contributes to myeloid cell growth
Quan-sheng Zhu,
Ling Xia,
Gordon B. Mills,
Clifford A. Lowell,
Ivo P. Touw, and
Seth J. Corey
From the Division of Pediatrics, University of Texas-M. D. Anderson Cancer Center; the Programs in Cancer Biology and Immunology, University of Texas-M. D. Anderson Cancer Center; the Department of Molecular Therapeutics, University of Texas-M. D. Anderson Cancer Center, Houston; the Department of Laboratory Medicine, University of California at San Francisco; the Department of Hematology, Erasmus University, Rotterdam, The Netherlands; and the Department of Leukemia, University of Texas-M. D. Anderson Cancer Center, Houston.
Granulocyte colony-stimulating factor (G-CSF) drives the production, survival, differentiation, and inflammatory functions of granulocytes. Reactive oxygen species (ROSs) provide a major thrust of the inflammatory response, though excessive ROSs may be deleterious. G-CSF stimulation showed a time- and dose-dependent increase in ROS production, correlating with activation of Lyn and Akt. Inhibition of Lyn, PI3-kinase, and Akt abrogated G-CSF-induced ROS production. This was also blocked by DPI, a specific inhibitor of NADPH oxidase. Following G-CSF stimulation, neutrophils from Lyn-/- mice produced less ROSs than wild-type littermates. G-CSF induced both serine phosphorylation and membrane translocation of p47phox, a subunit of NADPH oxidase. Because patients with a truncated G-CSF receptor have a high risk of developing acute myeloid leukemia (AML), we hypothesized that dysregulation of ROSs contributes to leukemogenesis. Cells expressing the truncated G-CSF receptor produced more ROSs than those with the full-length receptor. G-CSF-induced ROS production was enhanced in bone marrow-derived neutrophils expressing G-CSFR 715, a truncated receptor. The antioxidant N-acetyl-L-cysteine diminished G-CSF-induced ROS production and cell proliferation by inhibiting Akt activation. These data suggest that the G-CSF-induced Lyn-PI3K-Akt pathway drives ROS production. One beneficial effect of therapeutic targeting of Lyn-PI3K-kinase-Akt cascade is abrogating ROS production.
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