Deoxyribonucleic acid triplex formation inhibits granulocyte macrophage colony-stimulating factor gene expression and suppresses growth in juvenile myelomonocytic leukemic cells

The Journal of Clinical Investigation
M KochetkovaM F Shannon

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 protei...Continue Reading

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Citations

Jun 17, 2006·Journal of Clinical Immunology·Yashin SreenivasanSunil K Manna
Apr 28, 1999·Trends in Microbiology·S UgoliniQ J Sattentau
Oct 2, 2002·Journal of Biomolecular Structure & Dynamics·Mrinal Kanti GhoshRamesh Chandra
Aug 5, 2008·Nucleic Acids Research·Maria DucaPaola B Arimondo
Jan 20, 2012·Growth Factors·Timothy R HercusAngel F Lopez
May 21, 2009·Experimental and Molecular Pathology·Paula J BatesJohn O Trent
May 14, 2004·The Journal of Investigative Dermatology·Robert BeschKlaus Degitz
Oct 11, 2012·Immunological Reviews·Sophie E BroughtonMichael W Parker
Apr 11, 2014·BioMed Research International·Marianna GuidaAnto De Pol
Apr 21, 2001·Cell Death and Differentiation·F D'AcquistoR Carnuccio
Jun 22, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·D CakourosM F Shannon
Dec 18, 2001·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Per Ole IversenGeir Christensen
Oct 6, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Per Ole Iversen, Helge Wiig

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