THE FLT3 LIGAND POTENTLY AND DIRECTLY STIMULATES THE GROWTH AND EXPANSION OF PRIMITIVE MURINE BONE-MARROW PROGENITOR CELLS IN-VITRO - SYNERGISTIC INTERACTIONS WITH INTERLEUKIN (IL)-11, IL-12, AND OTHER HEMATOPOIETIC GROWTH-FACTORS

The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin(-)Sca-1(+)) and more committed (Lin(-)Sca-1(-)) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin(-)Sca-1(+), but not Lin(-)Sca-1(-) or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G-CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.