title: Dimerization of MLL fusion proteins immortalizes hematopoietic cells.
abstract: MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Martin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Milne
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bloyer
authors.forename: Karine
authors.initials: K
authors.lastname: Galoian
authors.forename: Weiping
authors.initials: W
authors.lastname: Shen
authors.forename: Denise
authors.initials: D
authors.lastname: Gibbs
authors.forename: Hugh W
authors.initials: HW
authors.lastname: Brock
authors.forename: Robert
authors.initials: R
authors.lastname: Slany
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D015973:Gene Expression Regulation, Leukemic; D006413:Hematopoietic System / Q000378:metabolism / Q000473:pathology*; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011519:Proto-Oncogenes; D012190:Retroviridae; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; C115962:HOXA7 protein, human; D018398:Homeodomain Proteins; C492047:Hoxa7 protein, mouse; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse