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.

• DOI: 10.1084/jem.181.4.1357
• Publication Date: 2004-06-24T07:56:10Z
• Authors: S E Jacobsen; C Okkenhaug; J Myklebust; O P Veiby; S D Lyman
• Keywords: 570; Stem Cell Factor; 0303 health sciences; Interleukin-6; Recombinant Fusion Proteins; 610; Receptor Protein-Tyrosine Kinases; Drug Synergism; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Interleukin-11; Interleukin-12; Rats; Mice, Inbred C57BL; Mice; 03 medical and health sciences; fms-Like Tyrosine Kinase 3; Proto-Oncogene Proteins; Radiation Chimera; Animals

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.