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|Title:||Deoxyribo-nucleic acid triplex formation inhibits granulocyte-macrophage colony-stimulating factor gene expression and suppresses growth in juvenile myelomonocytic leukemic cells.|
|Citation:||Journal of Clinical Investigation, 1997; 99(12):3000-3008|
|Publisher:||American Society for Clinical Investigation|
|Abstract:||Juvenile myelomonocytic leukemia (JMML) is a severe childhood malignancy. The autocrine production of GMCSF is believed to be responsible for the spontaneous proliferation of JMML cells. A nuclear factor-kappaB (NF-kappaB)/Rel binding site within the GM-CSF gene promoter, termed the kappaB element, plays an important role in controlling transcription from the GM-CSF gene. We investigated the effect of an oligonucleotide GM3, directed to form a DNA triple helix across this kappaB element, on growth and GM-CSF production by JMML cells. Treatment of these cells, either unstimulated or induced by TNFalpha, with GM3 led to a significant and specific inhibition of both GM-CSF production and spontaneous colony formation. This constitutes the first report linking specific triplex-mediated inhibition of gene transcription with a functional outcome; i.e., cell growth. We observed the constitutive presence of NF-kappaB/Rel proteins in the nucleus of JMML cells. The constitutive and TNFalpha-induced NF-kappaB/Rel complexes were identical and were composed mainly of p50 and c-Rel proteins. Treatment of the cells with a neutralizing anti-TNFalpha monoclonal antibody completely abrogated constitutive nuclear expression of NF-kappaB/Rel proteins. These results indicate that the aberrant, constitutive GM-CSF gene activation in JMML is maintained by TNFalpha-mediated activation of NF-kappaB/Rel proteins. Our findings identify the molecular basis for the autocrine TNFalpha activation of the GM-CSF gene in JMML and suggest potential novel and specific approaches for the treatment of this aggressive childhood leukemia.|
|Keywords:||Cell Nucleus; Humans; Leukemia, Myelomonocytic, Chronic; Tumor Necrosis Factor-alpha; NF-kappa B; Granulocyte-Macrophage Colony-Stimulating Factor; DNA; Oligodeoxyribonucleotides; Cell Division; Gene Expression; Binding Sites; Nucleic Acid Conformation; Child, Preschool; Infant; Sp1 Transcription Factor; Promoter Regions, Genetic|
|Appears in Collections:||Medicine publications|
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