title: Cooperative function of Aml1-ETO corepressor recruitment domains in the expansion of primary bone marrow cells.
abstract: AML1-ETO is an oncoprotein that can promote self-renewal of primary hematopoietic cells by opposing the activity of AML1. Two domains, Nervy-homology(NH) 2 and NH4, have been implicated in the recruitment of corepressors by AML1-ETO, but the relative roles of NH2 and NH4 vary in different cell lines and have not been examined in nonimmortalized cells. Here, we have used a series of differentiation, proliferation, and self-renewal assays in an effort to determine the roles of the NH domains using progenitor-enriched primary bone marrow cells. In these assays, deletion of NH2 or NH4, individually, has a minimal effect on AML1-ETO function, and the mutants retain the ability to promote long-term expansion of cells. In contrast, the double deletion of NH2 and NH4 eliminates the activity of the fusion protein. Thus, the double deletion of NH2 and NH4 produces a functional deficit greater than the sum of the individual deletions. These findings suggest that the NH2 and NH4 domains function cooperatively in the corepressor environment of primary bone marrow cells.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Hug
authors.forename: Samuel Y D
authors.initials: SY
authors.lastname: Lee
authors.forename: Erron L
authors.initials: EL
authors.lastname: Kinsler
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Lazar
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins; D014157:Transcription Factors