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
| Autor: | Jan Jacob Schuringa, Gwenny M. Fuhler, Edo Vellenga, Sandra Olthof, Paul J. Coffer, A. Lyndsay Drayer |
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| Přispěvatelé: | University of Groningen, Stem Cell Aging Leukemia and Lymphoma (SALL), Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| Rok vydání: | 2008 |
| Předmět: |
Adult
rho GTP-Binding Proteins Stromal cell MAP Kinase Signaling System Polymers Immunology Antigens CD34 HL-60 Cells NEUTROPHIL CHEMOTAXIS Biochemistry Phosphatidylinositol 3-Kinases Cell Movement Humans SIGNAL-REGULATED KINASE RESPIRATORY BURST Stromal cell-derived factor 1 Neural Tube Defects Progenitor cell PHOSPHORYLATION Protein kinase B Aged Aged 80 and over Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 ROLES Phosphoinositide 3-kinase biology Kinase STEM/PROGENITOR CELLS Cell Biology Hematology Middle Aged Actins Chemokine CXCL12 rac GTP-Binding Proteins HEMATOPOIETIC PROGENITOR CELLS Cell biology biology.protein Cancer research PHOSPHATIDYLINOSITOL 3-KINASE Stem cell Signal transduction MEDIATED INTERACTION Proto-Oncogene Proteins c-akt STEM-CELLS |
| Zdroj: | Blood, 111(1), 359-368. AMER SOC HEMATOLOGY |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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