title: ERG and FLI1 binding sites demarcate targets for aberrant epigenetic regulation by AML1-ETO in acute myeloid leukemia.
abstract: ERG and FLI1 are closely related members of the ETS family of transcription factors and have been identified as essential factors for the function and maintenance of normal hematopoietic stem cells. Here genome-wide analysis revealed that both ERG and FLI1 occupy similar genomic regions as AML1-ETO in t(8;21) AMLs and identified ERG/FLI1 as proteins that facilitate binding of oncofusion protein complexes. In addition, we demonstrate that ERG and FLI1 bind the RUNX1 promoter and that shRNA-mediated silencing of ERG leads to reduced expression of RUNX1 and AML1-ETO, consistent with a role of ERG in transcriptional activation of these proteins. Finally, we identify H3 acetylation as the epigenetic mark preferentially associated with ETS factor binding. This intimate connection between ERG/FLI1 binding and H3 acetylation implies that one of the molecular strategies of oncofusion proteins, such as AML1-ETO and PML-RAR-α, involves the targeting of histone deacetylase activities to ERG/FLI1 bound hematopoietic regulatory sites. Together, these results highlight the dual importance of ETS factors in t(8;21) leukemogenesis, both as transcriptional regulators of the oncofusion protein itself as well as proteins that facilitate AML1-ETO binding.
authors.affiliation: Radboud University, Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Joost H A
authors.initials: JH
authors.lastname: Martens
authors.forename: Amit
authors.initials: A
authors.lastname: Mandoli
authors.forename: Femke
authors.initials: F
authors.lastname: Simmer
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Wierenga
authors.forename: Sadia
authors.initials: S
authors.lastname: Saeed
authors.forename: Abhishek A
authors.initials: AA
authors.lastname: Singh
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.forename: Edo
authors.initials: E
authors.lastname: Vellenga
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
mesh_terms: D000107:Acetylation; D018952:Antigens, CD34 / Q000378:metabolism; D001665:Binding Sites; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D059372:Nucleotide Motifs; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D051789:Proto-Oncogene Protein c-fli-1 / Q000378:metabolism*; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D034622:RNA Interference; D000075142:RUNX1 Translocation Partner 1 Protein; D015534:Trans-Activators / Q000378:metabolism*; D000071230:Transcriptional Regulator ERG; D014178:Translocation, Genetic
chemical_list: C107844:AML1-ETO fusion protein, human; D018952:Antigens, CD34; D050676:Core Binding Factor Alpha 2 Subunit; C072312:ERG protein, human; D006657:Histones; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D050783:Proto-Oncogene Proteins c-ets; D000075142:RUNX1 Translocation Partner 1 Protein; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG