title: Redistribution of H3K27me3 and acetylated histone H4 upon exposure to azacitidine and decitabine results in de-repression of the AML1/ETO target gene IL3.
abstract: Human acute myeloid leukemia is characterized by a block in maturation caused by genetic and epigenetic alterations. We studied the effects of low concentrations of the DNA methyltransferase (DNMT) inhibitors 5-azacitidine and decitabine on apoptosis and on chromatin remodeling in an AML1/ETO inducible model of human AML. While both DNMT inhibitors induced apoptosis, only azacitidine did so via caspase activation, possibly through its exclusive non-DNA depending effects. We evaluated histone marks for permissive chromatin, H3K4me3, and acetylated histone H4, and for non-permissive chromatin, H3K9me2, and H3K27me3, at the promoter of the IL3 gene, which is under the direct control of AML1/ETO and is critical for myeloid maturation. We observed that low concentrations of DNMT inhibitors induced a loss of H3K27me3 and gain of acetylated histone H4 at the IL3 promoter exclusively in AML1/ETO-positive cells, which was associated with transcriptional reactivation of the IL3 gene.
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Buchi
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Erico
authors.initials: E
authors.lastname: Masala
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Ana
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Spinelli
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sanna
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gozzini
authors.affiliation: Hematology; University of Florence; AOU Careggi; Florence, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Santini
mesh_terms: D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D000077209:Decitabine; D020868:Gene Silencing / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics; D008745:Methylation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; C508596:IL3 protein, human; D007377:Interleukin-3; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C493728:RUNX1 protein, human; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine
keywords: AML1/ETO; H3K27me3; acetylated H4; acute myeloid leukemia; azacitidine; decitabine