title: AML1/ETO oncoprotein is directed to AML1 binding regions and co-localizes with AML1 and HEB on its targets.
abstract: A reciprocal translocation involving chromosomes 8 and 21 generates the AML1/ETO oncogenic transcription factor that initiates acute myeloid leukemia by recruiting co-repressor complexes to DNA. AML1/ETO interferes with the function of its wild-type counterpart, AML1, by directly targeting AML1 binding sites. However, transcriptional regulation determined by AML1/ETO probably relies on a more complex network, since the fusion protein has been shown to interact with a number of other transcription factors, in particular E-proteins, and may therefore target other sites on DNA. Genome-wide chromatin immunoprecipitation and expression profiling were exploited to identify AML1/ETO-dependent transcriptional regulation. AML1/ETO was found to co-localize with AML1, demonstrating that the fusion protein follows the binding pattern of the wild-type protein but does not function primarily by displacing it. The DNA binding profile of the E-protein HEB was grossly rearranged upon expression of AML1/ETO, and the fusion protein was found to co-localize with both AML1 and HEB on many of its regulated targets. Furthermore, the level of HEB protein was increased in both primary cells and cell lines expressing AML1/ETO. Our results suggest a major role for the functional interaction of AML1/ETO with AML1 and HEB in transcriptional regulation determined by the fusion protein.
authors.affiliation: Department of Experimental Oncology, IEO-European Institute of Oncology, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gardini
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.forename: Lucilla
authors.initials: L
authors.lastname: Luzi
authors.forename: Akiko J
authors.initials: AJ
authors.lastname: Okumura
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Biggs
authors.forename: Simone P
authors.initials: SP
authors.lastname: Minardi
authors.forename: Elisa
authors.initials: E
authors.lastname: Venturini
authors.forename: Dong-Er
authors.initials: DE
authors.lastname: Zhang
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000075142:RUNX1 Translocation Partner 1 Protein; D014158:Transcription, Genetic; D020298:U937 Cells
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; C107844:AML1-ETO fusion protein, human; C493728:RUNX1 protein, human; C073366:TCF12 protein, human