Effects of FLT3 ligand on human leukemia cells. II. Agonistic and antagonistic effects of other cytokines.
We have previously shown that the growth factor FLT3 ligand (FL) is mitogenic for human primary and continuously cultured myeloid leukemia cells. Despite widespread expression of the receptor FLT3 among the leukemia cell lines from certain cell lineages, only two growth factor-dependent myeloid leukemia cell lines showed a significant proliferative response to FL. In the present study, we examined the proliferative effects of FL on a comprehensive set of growth factor-dependent leukemia cell lines. A significant enhancement of cell growth by FL was seen in 10/12 myelomonocytic cell lines, while all cell lines with predominantly megakaryocytic and/or erythroid characteristics did not respond positively, despite the expression of the receptor. The cytokines interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and stem cell factor (SCF) could independently enhance the FL-stimulated proliferation in a synergistic fashion. Transforming growth factor-(beta)1 (TGF-(beta)1), in a dose-dependent fashion, partially inhibited the FL-promoted proliferation, but basic fibroblast growth factor (bFGF), on its own augmenting the response to FL, significantly abrogated 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 malignant hematopoietic cells can be positively and negatively modulated by other cytokines.
Dehmel
U
U
Department of Human and Animal Cell Cultures, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Quentmeier
H
H
Drexler
H G
HG
D015152:Blotting, Northern; D002455:Cell Division; D016207:Cytokines / Q000494:pharmacology*; D004357:Drug Synergism; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000473:pathology; D008565:Membrane Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019089:Stem Cell Factor / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000473:pathology
D016207:Cytokines; D007377:Interleukin-3; D008565:Membrane Proteins; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; C084881:flt3 ligand protein; D016222:Fibroblast Growth Factor 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor