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https://hdl.handle.net/2440/8944
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dc.contributor.author | Kocketkova, M. | - |
dc.contributor.author | Iversen, P. | - |
dc.contributor.author | Lopez, A. | - |
dc.contributor.author | Shannon, M. | - |
dc.date.issued | 1997 | - |
dc.identifier.citation | Journal of Clinical Investigation, 1997; 99(12):3000-3008 | - |
dc.identifier.issn | 0021-9738 | - |
dc.identifier.issn | 1558-8238 | - |
dc.identifier.uri | http://hdl.handle.net/2440/8944 | - |
dc.description.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. | - |
dc.language.iso | en | - |
dc.publisher | American Society for Clinical Investigation | - |
dc.source.uri | http://dx.doi.org/10.1172/jci119495 | - |
dc.subject | Cell Nucleus | - |
dc.subject | Humans | - |
dc.subject | Leukemia, Myelomonocytic, Chronic | - |
dc.subject | Tumor Necrosis Factor-alpha | - |
dc.subject | NF-kappa B | - |
dc.subject | Granulocyte-Macrophage Colony-Stimulating Factor | - |
dc.subject | DNA | - |
dc.subject | Oligodeoxyribonucleotides | - |
dc.subject | Cell Division | - |
dc.subject | Gene Expression | - |
dc.subject | Binding Sites | - |
dc.subject | Nucleic Acid Conformation | - |
dc.subject | Child, Preschool | - |
dc.subject | Infant | - |
dc.subject | Sp1 Transcription Factor | - |
dc.subject | Promoter Regions, Genetic | - |
dc.title | Deoxyribo-nucleic acid triplex formation inhibits granulocyte-macrophage colony-stimulating factor gene expression and suppresses growth in juvenile myelomonocytic leukemic cells. | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1172/JCI119495 | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Lopez, A. [0000-0001-7430-0135] | - |
Appears in Collections: | Aurora harvest Medicine publications |
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