Blood, Vol. 92 No. 11 (December 1), 1998:
pp. 4263-4268
Modulation of Granulocyte-Macrophage Colony-Stimulating Factor Gene
Expression by a Tumor Necrosis Factor 
Specific Ribozyme in Juvenile
Myelomonocytic Leukemic Cells
Per Ole Iversen and
Mouldy Sioud
From the Department of Physiology, Institute of Basic Medical
Sciences, University of Oslo, Oslo, Norway; and the Institute for
Cancer Research, Department of Immunology, the Norwegian Radium
Hospital, Oslo, Norway.
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-1
, 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.
