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 DNAmethylation, can modify chromatin and restore the ability of tumor necrosis factor A (TNFA) 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 TNFA-responsive promoters to facilitate TNFA-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFA 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-KB transcription factor in response to 5-AZAdC. Furthermore, 5-AZA-dC plus TNFA 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.

Inhibition of DNA methyltransferase activates tumor necrosis factor alpha-induced monocytic differentiation in acute myeloid leukemia cells / A. Laurenzana; L.A. Petruccelli; F. Pettersson; M.E. Figueroa; A. Melnick; A.S. Baldwin; F. Paoletti; W.H. Jr Miller. - In: CANCER RESEARCH. - ISSN 0008-5472. - STAMPA. - 69:(2009), pp. 55-64. [10.1158/0008-5472.CAN-08-0245]

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

LAURENZANA, ANNA;PAOLETTI, FRANCESCO;
2009

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 DNAmethylation, can modify chromatin and restore the ability of tumor necrosis factor A (TNFA) 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 TNFA-responsive promoters to facilitate TNFA-induced transcriptional pathways leading to differentiation. 5-AZA-dC regulates the expression of Dif-2, a TNFA 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-KB transcription factor in response to 5-AZAdC. Furthermore, 5-AZA-dC plus TNFA 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.
2009
69
55
64
A. Laurenzana; L.A. Petruccelli; F. Pettersson; M.E. Figueroa; A. Melnick; A.S. Baldwin; F. Paoletti; W.H. Jr Miller
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/339788
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