EFFECTS OF FLT3 LIGAND ON HUMAN LEUKEMIA-CELLS .2. AGONISTIC AND ANTAGONISTIC EFFECTS OF OTHER CYTOKINES

We have previously shown that the growth factor FLT3 ligand (FL) is mi togenic for human primary and continuously cultured myeloid leukemia c ells. Despite widespread expression of the receptor FLT3 among the leu kemia cell lines from certain cell lineages, only two growth factor-de pendent myeloid leukemia cell lines showed a significant proliferative response to FL. In the present study, we examined the proliferative e ffects of FL on a comprehensive set of growth factor-dependent leukemi a cell lines. A significant enhancement of cell growth by FL was seen in 10/12 myelomonocytic cell lines, while all cell lines with predomin antly megakaryocytic and/or erythroid characteristics did not respond positively, despite the expression of the receptor. The cytokines inte rleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM -CSF) and stem cell factor (SCF) could independently enhance the FL-st imulated proliferation in a synergistic fashion. Transforming growth f actor-beta 1 (TGF-beta 1), in a dose-dependent fashion, partially inhi bited the FL-promoted proliferation, but basic fibroblast growth facto r (bFGF), on its own augmenting the response to FL, significantly abro gated the inhibitory effects of TGF-beta 1. TGF-beta 1 down-regulated mRNA and protein expression of the FLT3 receptor, Taken together these data suggest that the effects of FL on the growth of normal and malig nant hematopoietic cells can be positively and negatively modulated by other cytokines.