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https://hdl.handle.net/2440/8944
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Type: | Journal article |
Title: | Deoxyribo-nucleic acid triplex formation inhibits granulocyte-macrophage colony-stimulating factor gene expression and suppresses growth in juvenile myelomonocytic leukemic cells. |
Author: | Kocketkova, M. Iversen, P. Lopez, A. Shannon, M. |
Citation: | Journal of Clinical Investigation, 1997; 99(12):3000-3008 |
Publisher: | American Society for Clinical Investigation |
Issue Date: | 1997 |
ISSN: | 0021-9738 1558-8238 |
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 |
DOI: | 10.1172/JCI119495 |
Appears in Collections: | Aurora harvest Medicine publications |
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