Effects of FLT3 ligand on proliferation and survival of myeloid leukemia cells.
FLT3 ligand (FL) acting through its tyrosine kinase receptor FLT3 has pleiotropic and potent effects on hematopoietic cells. The well-described involvement of this ligand-receptor pair in physiological hematopoiesis raised the question whether FL and FLT3 also play a role in the pathobiology of leukemia. Following the early discovery of high receptor expression by myeloid leukemia cells, several investigators have focused their attention on these cells, both primary acute myeloid leukemia (AML) cells and continuous human myeloid leukemia cell lines. Regardless of the morphological FAB subtype, the vast majority of AML cases were FLT3-positive both at the mRNA and protein level; among the myeloid cell lines, predominantly the monocytic and myelocytic cell lines were FLT3-positive whereas the erythrocytic and megakaryocytic cell lines were FLT3-negative. Virtually all cell lines studied expressed FL transcripts; the finding that some cell lines displayed both ligand and receptor indicates the possibility of autocrine, intracrine or paracrine stimulatory loops. In vitro growth assays showed that FL caused a proliferative response in a high percentage of AML cases. Only constitutively growth factor-dependent myelocytic cell lines increased their proliferation upon incubation with FL whereas all growth factor-independent cell lines were refractory to FL stimulation. Combinations of FL with various cytokines (e.g. G-CSF, GM-CSF, IL-3, M-CSF, PIXY-321, SCF) had synergistic or additive mitogenic effects. Finally, FL had significant anti-apoptotic, survival-promoting effects on primary AML cells and myeloid cell lines under serum-free culture conditions. On the strength of the above findings, it can be concluded that the FL-FLT3 signaling system may play a certain, albeit probably not causal role in the development of human leukemias. Dissection of the exact molecular pathways that lead to proliferation and/or anti-apoptosis of myeloid leukemia cells as well as the detailed elucidation of the possible contribution of the FL-FLT3 genes to leukemogenesis remain future challenges.
Drexler
H G
HG
The DSMZ-German Collection of Microorganism & Cell Cultures Department of Human and Animal Cell Cultures Braunschweig. hdr@gbf.de
Meyer
C
C
Quentmeier
H
H
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3
D000276:Adjuvants, Immunologic; D016207:Cytokines; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C084881:flt3 ligand protein; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3