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Ann Hematol. 2005 Dec;84 Suppl 1:54-60.

Butyrates and decitabine cooperate to induce histone acetylation and granulocytic maturation of t(8;21) acute myeloid leukemia blasts.

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1
UF Ematologia, Università degli Studi di Firenze, Policlinico di Careggi, Florence, Italy.

Abstract

Core histones are proteins organized in octamers, to which DNA is wrapped more or less tightly, depending on their acetylation status. Gene transcription is regulated by a complex series of epigenetic modifications, i.e., histone modification such as methylation and acetylation, events determined by the enzymatic activity of histone methyltransferases, and histone acetyltransferases, respectively, the latter counterbalanced by histone deacetylases (HDAC). Acetylation of histones facilitates destabilization of DNA-nucleosome interaction and renders DNA more accessible to transcription factors. Methylation of different specific lysine residues of histones is differently linked to euchromatin (transcripted DNA) or heterochromatin (silenced DNA). On the other hand, methylation of the promoter regions of some genes by DNA methyltransferases (DNMT) leads to transcriptional silencing and is a common mechanism to regulate gene expression. In normal eukaryotic cells, DNA methylation and histone acetylation are interdependent and maintain equilibrium, allowing temporal expression of genes. In neoplastic cells, this balance is frequently disrupted. In leukemic cells, hypermethylation of CpG islands in the promoter region of genes critical for cell cycle and maturation is frequent, and DNMTs were found to be overexpressed, findings paralleled by evidence of transcriptional repression of downstream genes. Therefore, the combination of HDAC and DNMT inhibitors has been considered to be a possible therapeutic approach to restore normal gene expression in acute myeloid leukemia (AML) and other diseases. Human AML1/ETO Kasumi cells were exposed to the HDAC inhibitor D1 (O-n-butanoil-2,3-O-isopropylidene-alpha-D: -mannofuranoside) and 5-aza-deoxycytidine (decitabine) alone and in combination. Histone acetylation as measured by flow cytometry was increased following treatment with D1 and the combination of D1 and decitabine. Addition of D1 alone or in combination with decitabine also led to inhibition of cell proliferation and induction of apoptosis. Thus, treatment of AML with HDAC inhibitors such as D1 and DNMT inhibitors such as decitabine might have clinical benefit for patients, especially these presenting subtypes of AML, like AML1/ETO, in which the leukemogenic mechanism involves corepressor protein complexes containing HDAC and DNMT.

PMID:
16228241
DOI:
10.1007/s00277-005-0006-z
[Indexed for MEDLINE]
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