MODULATION OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR GENE-EXPRESSION BY A TUMOR-NECROSIS-FACTOR-ALPHA SPECIFIC RIBOZYME IN JUVENILE MYELOMONOCYTIC LEUKEMIC-CELLS

The human cytokines tumor necrosis factor alpha (TNF alpha) and granul ocyte-macrophage colony-stimulating factor (GMCSF) both promote growth and survival of malignant cells from children with juvenile myelomono cytic leukemia (JMML). It has been postulated that TNF alpha stimulate s GMCSF gene expression in an autocrine manner. We found here that the specific inhibition of TNF alpha gene expression by a catalytic RNA m olecule (ribozyme) also downregulated the expression of GM-CSF in JMML cells. GM-CSF protein, GM-CSF-dependent colony formation, and viabili ty of JMML cells were reduced. The observed effect was specific, becau se synthesis of interleukin-1 beta, another cytokine produced by JMML cells, was not affected by the ribozyme treatment. The stimulatory eff ect of TNF alpha on GM-CSF gene expression in JMML cells probably take s place at the transcription level, because the ribozyme treatment dec reased GM-CSF mRNA. No apparent toxicity of the ribozyme was detected in normal bone marrow progenitor cells. Thus, the inhibition of TNF al pha gene expression in JMML cells by ribozymes may be a novel therapeu tic approach for this disorder. (C) 1998 by The American Society of He matology.