Paracrine and autocrine growth mechanisms of human stem cell factor (c-kit ligand) in myeloid leukemia.
A novel hematopoietic growth factor, the stem cell factor (SCF), for primitive hematopoietic progenitor cells has recently been purified and its gene has been cloned. In this study, the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor was tested. The proliferation of myeloid leukemia cell lines as well as fresh myeloid leukemic blasts from patients was investigated in a 72 h 3H-thymidine uptake assay in the presence of various concentrations of rhSCF alone or in combination with saturating concentrations of G-CSF, GM-CSF, M-CSF, IL-3, or erythropoietin (EPO). Only five out of 30 lines, but fresh leukemic blasts from 75% of the AML blast samples significantly responded to SCF. To determine the SCF binding sites on leukemic cells, 125I-radiolabelled SCF was used in Scatchard analysis and cross-linking studies. Crosslinking studies demonstrated a 150 kD SCF receptor on the surface of some myeloid leukemic cell lines and all blast preparations. The response to SCF did not correlate to the receptor numbers expressed on the cell surface or to a certain subtype of myeloid leukemia. Using PCR analysis of total RNA from the myeloid leukemia lines we found coexpression of SCF-mRNA and SCF receptor-mRNA in 29% of the myeloid leukemia lines. Soluble as well as membrane bound SCF protein was found to be expressed in myeloid leukemia cells by monoclonal antibodies generated against SCF. This suggests autocrine mechanisms in the growth of a subgroup of leukemic cells by coexpression of SCF and its receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Pietsch
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Institute of Neuropathology, University of Bonn, Germany.
D004921:Erythropoietin / Q000502:physiology; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology; D016298:Hematopoietic Cell Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000502:physiology; D007951:Leukemia, Myeloid / Q000097:blood*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit; D016184:Receptors, Colony-Stimulating Factor / Q000502:physiology; D019089:Stem Cell Factor
D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D016184:Receptors, Colony-Stimulating Factor; D019089:Stem Cell Factor; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019009:Proto-Oncogene Proteins c-kit