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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.
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Submitted April 16, 2004
Accepted December 20, 2004
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
Department of Microbiology & Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA
Department of Microbiology & Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, IN, USA; Walther Cancer Institute, Indianapolis, IN, USA
* Corresponding author; email: sfukuda{at}iupui.edu.
Flt3 ligand (FL) enhances hematopoietic cell proliferation and facilitates hematopoietic stem cell mobilization in vivo, while the SDF-1 (CXCL12)/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, over-expression of constitutively-activated ITD-Flt3 mutants in Ba/F3 cells dramatically enhanced migration towards CXCL12. In Ba/F3-Flt3 cells, synergistic cell migration to FL plus CXCL12 was associated with enhanced phosphorylation of MAPKp42/p44, CREB and Akt and was partially inhibited by pretreatment of cells with selective inhibitors for MAPKp42/p44, PKA or 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 towards 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.
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