TitleInhibition of DNA methyltransferase activates tumor necrosis factor alpha-induced monocytic differentiation in acute myeloid leukemia cells.
Publication TypeJournal Article
Year of Publication2009
AuthorsLaurenzana, Anna, Petruccelli Luca A., Pettersson Filippa, Figueroa Maria Eugenia, Melnick Ari, Baldwin Albert S., Paoletti Francesco, and Miller Wilson H.
JournalCancer Res
Volume69
Issue1
Pagination55-64
Date Published2009 Jan 01
ISSN1538-7445
KeywordsAcetylation, Acute Disease, Azacitidine, Cell Differentiation, Chromatin, Decitabine, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Enzyme Inhibitors, Histones, Humans, Leukemia, Myeloid, Monocytes, NF-kappa B, NF-kappa B p50 Subunit, Promoter Regions, Genetic, Receptors, Tumor Necrosis Factor, Type I, Receptors, Tumor Necrosis Factor, Type II, Transcription Factor RelA, Tumor Necrosis Factor-alpha, U937 Cells
Abstract

<p>Transcriptional silencing via promoter methylation of genes important for cell growth and differentiation plays a key role in myeloid leukemogenesis. We find that clinically achievable levels of 5-aza-2'-deoxycytidine (5-AZA-dC), a potent inhibitor of DNA methylation, can modify chromatin and restore the ability of tumor necrosis factor alpha (TNFalpha) to induce monocytic differentiation of the acute myeloid leukemia cells NB4 and U937. Although 5-AZA-dC cannot fully induce differentiation, we show that 5-AZA-dC acts directly on TNFalpha-responsive promoters to facilitate TNFalpha-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFalpha target gene, by deacetylating chromatin domains in a methylation-dependent manner. Chromatin immunoprecipitation analyses of the Dif-2 promoter show histone hyperacetylation and a recruitment of the nuclear factor-kappaB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFalpha enhances the level of phosphorylated RNA Pol II at the Dif-2 promoter via synergistic recruitment of TFIIH. We conclude that nonspecific changes in chromatin can allow a specific transcriptional inducer to overcome blocks in leukemic cell differentiation. Our results support the concept of low doses of 5-AZA-dC acting in combination with other agents to target epigenetic changes that drive malignant growth in leukemic cells. [Cancer Res 2009;69(1):55-64].</p>

DOI10.1158/0008-5472.CAN-08-0245
Alternate JournalCancer Res
PubMed ID19117987