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

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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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