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The FLT3/FLK2 ligand: structure, functions and prospects Volume 9, issue 1, March 1998

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Hematopoiesis is a tightly regulated process which involves positive and negative signals mediated by either soluble hematopoietic growth factors (HGFs) or cell-cell interactions [1, 2]. Throughout life, the hematopoietic system is continuously regenerated from a limited number of stem cells, the pluripotent hematopoietic stem cells (HSCs). HGFs as well as cellular and extracellular microenvironments influence the proliferation and differentiation of HSCs and their progeny [1-5]. Most human (and primate) HSCs express the CD34 antigen a feature which is currently used for the separation, purification and analysis of these cells [6-8], although a very recent report has clearly demonstrated that a small minority of very primitive HSCs (possibly pre-CD34 cells), which do not express the CD34 antigen, can be isolated from human or primate bone marrow [9]. The most primitive progenitors among HSCs, cells (human CD34+/CD38­/CD71low/HLA-DRlow/ c-kitlow/lin­, and murine Sca-1+/Lin­/CD71­/ c-kitlow/class Ihigh) can only be recruited to proliferate in vitro by the combined presence of several HGFs. This synergistic activity of HGFs, essential for the stimulation of pluripotent HSCs, can also result in enhanced proliferation and differentiation of committed progenitors even if these progenitors may themselves be stimulated by a single cytokine [1, 2]. A number of HGFs have only little or no proliferative activity when used alone, but predominantly enhance growth activities of other HGFs. Stem cell factor (SCF) (also known as c-kit ligand or Steel factor) and FLT3/FLK2 ligand (FL) are members of this group of synergistic "early acting" cytokines. The growth promoting activity of SCF on pluripotent HSCs and on committed progenitors of the erythroid, myeloid, mast and megakaryocytic lineages has been well demonstrated in murine as well as in human hematopoiesis. Generation of lymphoid B cells, natural killer cells and dendritic cells can be also efficiently enhanced thanks to the potent synergistic activity of SCF, when combined with specific cytokines [see 10, for a recent review].