title: Chromatin modifications induced by the AML1-ETO fusion protein reversibly silence its genomic targets through AML1 and Sp1 binding motifs.
abstract: The AML1-ETO fusion protein, which is present in 10-15% of cases of acute myeloid leukemia, is known to repress myeloid differentiation genes through DNA binding and recruitment of chromatin-modifying proteins and transcription factors in target genes. ChIP-chip analysis of human hematopoietic stem/progenitor cells transduced with the AML1-ETO fusion gene enabled us to identify 1168 AML1-ETO target genes, 103 of which were co-occupied by histone deacetylase 1 (HDAC1) and had lost the hyperacetylation mark at histone H4, and 264 showed a K9 trimethylation at histone H3. Enrichment of genes involved in hematopoietic differentiation and in specific signaling pathways was observed in the presence of these epigenetic modifications associated with an 'inactive' chromatin status. Furthermore, AML1-ETO target genes had a significant correlation between the chromatin marks studied and transcriptional silencing. Interestingly, AML1 binding sites were absent on a large number of selected AML1-ETO promoters and an Sp1 binding site was found in over 50% of them. Reversible silencing induced by the fusion protein in the presence of AML1 and/or Sp1 transcription factor binding site was confirmed. Therefore, this study provides a global analysis of AML1-ETO functional chromatin modifications and identifies the important role of Sp1 in the DNA binding pattern of AML1-ETO, suggesting a role for Sp1-targeted therapy in this leukemia subtype.
authors.affiliation: Molecular Cytogenetics Group, Human Cancer Genetics programme, Centro Nacional Investigaciones Oncologicas, Centro de Investigaciones de Enfermedades Raras, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Maiques-Diaz
authors.forename: F S
authors.initials: FS
authors.lastname: Chou
authors.forename: M
authors.initials: M
authors.lastname: Wunderlich
authors.forename: G
authors.initials: G
authors.lastname: Gómez-López
authors.forename: F V
authors.initials: FV
authors.lastname: Jacinto
authors.forename: S
authors.initials: S
authors.lastname: Rodriguez-Perales
authors.forename: M J
authors.initials: MJ
authors.lastname: Larrayoz
authors.forename: M J
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: J C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: J C
authors.initials: JC
authors.lastname: Cigudosa
authors.forename: S
authors.initials: S
authors.lastname: Alvarez
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D050676:Core Binding Factor Alpha 2 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic; D023281:Genomics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D060888:Real-Time Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014470:Umbilical Cord / Q000166:cytology / Q000378:metabolism
chemical_list: C107844:AML1-ETO fusion protein, human; D002843:Chromatin; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D012333:RNA, Messenger; D000075142:RUNX1 Translocation Partner 1 Protein; D016329:Sp1 Transcription Factor; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1