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Reduced activation of protein kinase B, Rac, and F-actin polymerization contributes to an impairment of stromal cell derived factor-1 induced migration of CD34+ cells from patients with myelodysplasia

Fuhler, Gwenny M., Drayer, A. Lyndsay, Olthof, Sandra G. M., Schuringa, Jan Jacob, Coffer, Paul J., Vellenga, Edo·2008·Blood

Abstract

Patients with myelodysplasia (MDS) show a differentiation defect in the multipotent stem-cell compartment. An important factor in stem-cell differentiation is their proper localization within the bone marrow microenvironment, which is regulated by stromal cell–derived factor (SDF-1). We now show that SDF-1–induced migration of CD34+ progenitor cells from MDS patients is severely impaired. In addition, these cells show a reduced capacity to polymerize F-actin in response to SDF-1. We demonstrate a major role for Rac and phosphatidylinositol 3-kinase (PI3K) and a minor role for the extracellular signal-regulated kinase (ERK)1/2 signaling pathway in SDF-1–induced migration of normal CD34+ cells. Furthermore, SDF-1–stimulated activation of Rac and the PI3K target protein kinase B is impaired in CD34+ cells from MDS patients. Lentiviral transduction of MDS CD34+ cells with constitutive active Rac1V12 results in a partial restoration of F-actin polymerization in response to SDF-1. In addition, expression of constitutive active Rac increases the motility of MDS CD34+ cells in the absence of SDF-1, although the directional migration of cells toward this chemoattractant is not affected. Taken together, our results show a reduced migration of MDS CD34+ cells toward SDF-1, as a result of impaired activation of the PI3K and Rac pathways and a decreased F-actin polymerization.

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Crossref · 10.1182/blood-2006-11-060632

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Cited by

Metadata

Authors
Fuhler, G. M., Drayer, A. L., Olthof, S. G. M., Schuringa, J. J., Coffer, P. J., & Vellenga, E.
Affiliations
  • Division of Hematology, Department of Medicine, University Medical Center Groningen, Groningen;
  • Sanquin Blood Bank North East Netherlands, Groningen; and
  • Department of Immunology, University Medical Center Utrecht, the Netherlands
Venue
Blood
Published
2008-01-01
Volume
111
Issue
1
Pages
359-368
ISSN
  • 0006-4971
  • 1528-0020
Cited by
36
References
0
Language
en

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