Regulation of FLT3 and its ligand in normal hematopoietic progenitor cells.
FLT3 and its ligand (FL) are one of the regulators of normal hematopoiesis. Ligand-independent activation of FLT3 occurs in about 30% of acute myeloid leukemia cases and is one goal for selectively targeted therapies. However, the function of FLT3/FL in the regulation of non-malignant immature hematopoietic cells is poorly characterized. In order to elucidate the role of FLT3 in normal hematopoiesis, human adult CD34(+) hematopoietic progenitor cells were cultured in cytokine-supplemented liquid culture in the presence or absence of FLT3 inhibition by CEP-701 (lestaurtinib). Total cell number, lineage-committed, and primitive progenitors and apoptosis were assayed. FLT3 expression and FL secretion in various conditions were analyzed by fluorescent activated cell sorter and enzyme-linked immunosorbent assay. Effects of nonspecific targeting of FLT3 were evaluated with addition of imatinib (Gleevec) to cell cultures. It is demonstrated that FLT3 inhibition impaired cell and progenitor cell growth and increased the rate in apoptosis. Effects were observed independent of addition of FL. The dose-dependent growth inhibition was partially equalized by inhibiting FL with a neutralizing antibody. FLT3 inhibition resulted in markedly increased production of FL by cultured CD34(+) cells as well as upregulation of FLT3 expression. Imatinib mimicked effects of selective FLT3 inhibition. In conclusion, FLT3 and its ligand regulate proliferation of hematopoietic progenitor cells in an autocrine/paracrine manner Nonspecific inhibition of FLT3 may contribute to hematotoxicity caused by imatinib treatment.
Weisel
Katja C
KC
Medical Center, Department of Hematology, Oncology and Immunology, University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany. katja.weisel@med.uni-tuebingen.de
Yildirim
Sedat
S
Schweikle
Eric
E
Kanz
Lothar
L
Möhle
Robert
R
D002227:Carbazoles / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005663:Furans; D006410:Hematopoiesis / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*
D002227:Carbazoles; D005663:Furans; D008565:Membrane Proteins; C084881:flt3 ligand protein; C119379:lestaurtinib; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3