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Blood, 15 April 2005, Vol. 105, No. 8, pp. 3117-3126. Prepublished online as a Blood First Edition Paper on December 23, 2004; DOI 10.1182/blood-2004-04-1440. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-04-1440v1 105/8/3117    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fukuda, S. Articles by Pelus, L. M. Search for Related Content PubMed PubMed Citation Articles by Fukuda, S. Articles by Pelus, L. M. Related Collections Hematopoiesis and Stem Cells Cell Adhesion and Motility Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMATOPOIESIS Flt3 ligand and the Flt3 receptor regulate hematopoietic cell migration by modulating the SDF-1(CXCL12)/CXCR4 axis Seiji Fukuda, Hal E. Broxmeyer, and Louis M. Pelus From the Department of Microbiology & Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN; and the Walther Cancer Institute, Indianapolis, IN. Flt3 ligand (FL) enhances hematopoietic cell proliferation and facilitates hematopoietic stem cell mobilization in vivo, while the stromal-derived factor 1 (SDF-1, CXC ligand 12 [CXCL12])/CXC receptor 4 (CXCR4) axis is critical for their homing and trafficking. We investigated if FL and its receptor, Flt3, functionally interact with CXCL12/CXCR4 to regulate hematopoietic cell migration. FL stimulated chemokinetic activity when used alone, but synergistically enhanced short-term migration of CD34+ cells, Ba/F3 cells expressing human Flt3 (Ba/F3-Flt3), and human RS4;11 acute leukemia cells, induced by CXCL12. Moreover, overexpression of constitutively activated internal tandem duplication (ITD)–Flt3 mutants in Ba/F3 cells dramatically enhanced migration toward CXCL12. In Ba/F3-Flt3 cells, synergistic cell migration to FL plus CXCL12 was associated with enhanced phosphorylation of mitogen-activated protein kinase p42/p44 (MAPKp42/p44), cyclic adenosine monophosphate response element binding protein (CREB), and Akt, and was partially inhibited by pretreatment of cells with selective inhibitors for MAPKp42/p44, protein kinase A (PKA), or phosphatidylinositol 3–kinase (PI3-kinase), implicating these pathways in migration to FL plus CXCL12. In contrast, prolonged exposure of CD34+ or Ba/F3-Flt3 cells to FL down-regulated CXCR4 expression, inhibited CXCL12-mediated phosphorylation of MAPKp42/p44, CREB, and Akt, and impaired migration toward CXCL12. These findings suggest that FL/Flt3 may facilitate hematopoietic cell migration/homing and mobilization by enhancing or inhibiting CXCL12/CXCR4 signaling pathways and that the FL/Flt3 axis participates in trafficking of normal and transformed hematopoietic cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Z. Shao, T. O. Makinde, H. S. McGee, X. Wang, and D. K. Agrawal Fms-Like Tyrosine Kinase 3 Ligand Regulates Migratory Pattern and Antigen Uptake of Lung Dendritic Cell Subsets in a Murine Model of Allergic Airway Inflammation J. Immunol., December 1, 2009; 183(11): 7531 - 7538. [Abstract] [Full Text] [PDF] S. Fukuda, P. Singh, A. Moh, M. Abe, E. M. Conway, H. S. Boswell, S. 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W. Wlodarski, and J. P. Maciejewski Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis Blood, June 15, 2006; 107(12): 4834 - 4840. [Abstract] [Full Text] [PDF] S. Fukuda, H. Bian, E. M. Conway, and L. M. Pelus The Survivin/p21WAF1/Cip1 Axis and the CXC Chemokine SDF1{alpha} Regulate Growth Factor Independent Survival of Primary Hematopoietic Progenitor Cells Induced by Internal Tandem Duplication Mutations of Flt3. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 1611 - 1611. [Abstract]

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