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Activation of the fibromyalgia syndrome-like tyrosine kinase 3 ( FLT3) by its ligand, FLT3 ligand ( FL), strongly augments the development of natural killer ( NK) cells from human CD34+ hematopoietic progenitor cells ( HPCs) in the presence of IL-15, compared with NK-cell development in the presence of IL-15 alone. In this study, we observed that blocking the receptor tyrosine kinase Axl/ Gas6 pathway with a soluble Axl-IgG1 Fc fusion protein ( Axl- Fc) in the presence of FL significantly diminished the absolute number of CD3− CD56+ NK cells derived from human CD34+ HPCs. Axl- Fc reduced the expression levels of the IL-2/15 receptor β chain ( CD122) and γ chain ( CD132) induced by activation of FLT3 and consequently reduced the frequency of NK precursor cells responding to IL-15. Furthermore, Axl- Fc diminished FL-induced FLT3 phosphorylation and impeded the physical interaction between Axl and FLT3 in CD34+ HPCs. Collectively, our data suggest that the Axl/ Gas6 pathway contributes to normal human NK-cell development at least in part via its positive regulatory effect on FLT3 signaling in CD34+ HPCs. [ABSTRACT FROM AUTHOR]