Actions of Flt-3/Flk-2 Ligand on B Cell Lymphopoiesis in Bone Marrow

Flt-3/Flk-2 Ligand (Fl, or Flt3-L) is a transmembrane 30 kDa glycoprotein that binds and activates the Flt3 receptor. Flt-3 receptor is a member of the class III subfamily of receptor tyrosine kinase (RTK) that also include c-kit (stem cell factor receptor), c-fms share strong structural similarities and all three are involved in hematapoieses. Expression of Flt-3 is primarily restricted among hematopoietic cells to the most primitive progenitor cells. Fl is structurally related to M-CSF (CSF-1) and SCF (KL) with all three sharing a similar size, existence of transmembrane and soluble forms, four conserved cysteines (six for FL and M-CSF), and alternative splicing exon locations, but they share little sequence homology. The protein, which is biologically active on the cell surface and can be cleaved to generate a soluble form that is also biologically active. The most abundant isoform in mouse is a membrane attached (but not transmembrane) protein which has not been identified in human cDNA. The third isoform of FL is an alternatively spliced soluble form found in both human and mouse. FL of mouse and human share 72% amino acid sequence homology and exhibit full species cross-reactivity. Human FL is active on mouse, rat, cat rabbit, primate, and human cells. FL is widely expressed in various human and mouse tissues. In vitro studies, show that FL has relatively few effects by itself on the proliferation and differentiation of hematopoietic cells, but exhibits a potent costimulatory activity in enhancing proliferation of progenitor cells of costimulatory activity in enhancing proliferation of progenitor cells of multiple lineages. FL promotes the growth of clonogenic myeloid progenitor cells in the presence of other cytokines known to be active on myeloid progenitors, including GM-SCF, IL-3, SCF (KL), M-CSF and G-CSF. In addition, FL acts in synergy with IL-7 to induce proliferation of pro-B cells. FL has little effect on the growth of clonogenic erythroid progenitors. FL may play an indirect role in development of human leukemias.

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