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Published online before print November 1, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0506311

Received for publication May 9, 2006.
Revised September 20, 2006.
Accepted for publication September 21, 2006.

Article

The reduced GM-CSF priming of ROS production in granulocytes from patients with Myelodysplasia is associated with an impaired lipid raft formation

Gwenny M. Fuhler ^*, Nel R. Blom ^*, Paul J. Coffer , A. Lyndsay Drayer , and Edo Vellenga ^*@

*Division of Hematology, Department of Medicine, University Medical Center Groningen, Groningen, the Netherlands; Laboratory of Cell Biology and Electron Microscopy, University of Groningen, Groningen, the Netherlands; Department of Immunology, University Medical Center Utrecht, Utrecht, the Netherlands; and Sanquin Blood Bank North East Netherlands, Groningen, the Netherlands

^@ To whom correspondence should be addressed. E-mail: E.Vellenga{at}int.umcg.nl.

	Abstract

Patients with Myelodysplasia show an impaired reactive oxygen species (ROS) production in response to fMLP stimulation of GM-CSF-primed neutrophils. In this study, we investigated the involvement of lipid rafts in this process and showed that treatment of neutrophils with the lipid raft-disrupting agent methyl--cyclodextrin abrogates fMLP-induced ROS production and activation of ERK1/2 and protein kinase B/Akt, two signal transduction pathways involved in ROS production in unprimed and GM-CSF-primed neutrophils. We subsequently showed that there was a decreased presence of Lyn, p91^phox, and p22^phox in lipid raft fractions from neutrophils of Myelodysplastic syndromes (MDS). Furthermore, the plasma membrane expression of the lipid raft marker GM1, which increases upon stimulation of GM-CSF-primed cells with fMLP, was reduced significantly in MDS patients. By electron microscopy, we showed that the fMLP-induced increase in GM1 expression in GM-CSF-primed cells was a result of de novo synthesis, which was less efficient in MDS neutrophils. Taken together, these data indicate an involvement of lipid rafts in activation of signal transduction pathways leading to ROS production and show that in MDS neutrophils, an impaired lipid raft formation in GM-CSF-primed cells results in an impaired ROS production.

Key Words: MDS • signal transduction • NADPH

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