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Blood, 1 February 2003, Vol. 101, No. 3, pp. 1172-1180
PHAGOCYTES
Decreased phosphorylation of protein kinase B and extracellular
signal-regulated kinase in neutrophils from patients with
myelodysplasia
Gwenny M. Fuhler,
A.
Lyndsay Drayer, and
Edo Vellenga
From the Division of Hematology, Department of
Medicine, University Hospital Groningen, The Netherlands,
and the Blood Bank Noord Nederland, Groningen, The
Netherlands.
Neutrophils from patients with myelodysplastic syndrome (MDS) show
a disturbed differentiation pattern and are generally dysfunctional. To
study these defects in more detail, we investigated reactive-oxygen species (ROS) production and F-actin polymerization in neutrophils from
MDS patients and healthy controls and the involvement of N-formyl-L-methionyl-L-lucyl-L-phenylaline (fMLP) and granulocyte macrophage-colony-stimulating factor (GM-CSF)-stimulated signal transduction pathways. Following fMLP stimulation, similar levels of respiratory burst, F-actin polymerization, and activation of the
small GTPase Rac2 were demonstrated in MDS and normal neutrophils. However, GM-CSF and G-CSF priming of ROS production were significantly decreased in MDS patients. We subsequently investigated the signal transduction pathways involved in ROS generation and demonstrated that
fMLP-stimulated ROS production was inhibited by the
phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002, but not by the
MAPK/ERK kinase (MEK) inhibitor U0126. In contrast, ROS
production induced by fMLP stimulation of GM-CSF-primed cells was
inhibited by LY294002 and U0126. This coincides with enhanced protein
kinase B (PKB/Akt) phosphorylation that was PI3K dependent and enhanced
extracellular signal-regulated protein kinase 1 and 2 (ERK1/2)
phosphorylation that was PI3K independent. We demonstrated higher
protein levels of the PI3K subunit p110 in neutrophils from MDS
patients and found that though the fMLP-induced phosphorylation of
PKB/Akt and ERK1/2 could also be enhanced by pretreatment with GM-CSF in these patients, the degree and kinetics of PKB/Akt and ERK1/2 phosphorylation were significantly disturbed. These defects were observed despite a normal GM-CSF-induced signal transducer and activator of transcription 5 (STAT5) phosphorylation. Our results indicate that the reduced priming of neutrophil ROS production in MDS
patients might be caused by a disturbed convergence of the fMLP and
GM-CSF signaling routes.
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