Inhibition of DNA methyltransferase activates tumor necrosis factor α-induced monocytic differentiation in acute myeloid leukemia cells

Anna Laurenzana, Luca A. Petruccelli, Filippa Pettersson, Maria Eugenia Figueroa, Ari Melnick, Albert S. Baldwin, Francesco Paoletti, Wilson H. Miller

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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 α (TNFα) 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 TNFα-responsive promoters to facilitate TNFα-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFα 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-κB transcription factor in response to 5-AZA-dC. Furthermore, 5-AZA-dC plus TNFα enhances the level of phosphorylated RNAP ol 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.

Original languageEnglish (US)
Pages (from-to)55-64
Number of pages10
JournalCancer Research
Volume69
Issue number1
DOIs
StatePublished - Jan 1 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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