Modulation of granulocyte-macrophage colony-stimulating factor gene expression by a tumor necrosis factor α specific ribozyme in juvenile myelomonocytic leukemic cells

The human cytokines tumor necrosis factor alpha (TNF alpha) and granulocyte-macrophage colony-stimulating factor (GMCSF) both promote growth and survival of malignant cells from children with juvenile myelomonocytic leukemia (JMML). It has been postulated that TNF alpha stimulates GMCSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF alpha 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 beta, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory effect of TNF alpha 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 alpha gene expression in JMML cells by ribozymes may be a novel therapeutic approach for this disorder. (C) 1998 by The American Society of Hematology.