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Blood, 1 January 2008, Vol. 111, No. 1, pp. 359-368.
Prepublished online as a Blood First Edition Paper on September 26, 2007; DOI 10.1182/blood-2006-11-060632.
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Submitted November 30, 2006
Accepted September 18, 2007
Reduced activation of protein kinase B, Rac and F-actin polymerisation contribute to an impairment of SDF-1-induced migration of CD34+ cells from patients with Myelodysplasia
Gwenny M Fuhler, A. Lyndsay Drayer, Sandra G.M. Olthof, Jan Jacob Schuringa, Paul J. Coffer, and Edo Vellenga*
Division of Hematology Research, Department of Medicine, University Hospital Groningen, Groningen, Netherlands
Sanquin Blood Bank North East Netherlands, Groningen, Netherlands
University of Groningen, Groningen, Netherlands
Department of Immunology, University Medical Center Utrecht, Utrecht, Netherlands
* Corresponding author; email: e.vellenga{at}int.umcg.nl.
Patients with Myelodysplasia (MDS) show a differentiation defect in the multipotent stem cell compartment. An important factor in stem cell differentiation is their proper localisation 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 polymerise 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 ERK1/2 signalling 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 polymerisation 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 towards this chemoattractant is not affected. Taken together, our results show a reduced migration of MDS CD34+ cells towards SDF-1, as a result of impaired activation of the PI3K and Rac pathways and a decreased F-actin polymerisation.
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