Modulation of granulocyte-macrophage colony-stimulating factor gene expression by a tumor necrosis factor specific ribozyme in juvenile myelomonocytic leukemic cells.
The human cytokines tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) both promote growth and survival of malignant cells from children with juvenile myelomonocytic leukemia (JMML). It has been postulated that TNF stimulates GM-CSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF gene expression by a catalytic RNA molecule (ribozyme) also downregulated the expression of GM-CSF in JMML cells. GM-CSF protein, GM-CSF-dependent colony formation, and viability of JMML cells were reduced. The observed effect was specific, because synthesis of interleukin-1beta, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory effect of TNF on GM-CSF gene expression in JMML cells probably takes place at the transcription level, because the ribozyme treatment decreased GM-CSF mRNA. No apparent toxicity of the ribozyme was detected in normal bone marrow progenitor cells. Thus, the inhibition of TNF gene expression in JMML cells by ribozymes may be a novel therapeutic approach for this disorder.
Iversen
P O
PO
Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Sioud
M
M
D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics*; D008969:Molecular Sequence Data; D016337:RNA, Catalytic / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D016337:RNA, Catalytic; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor