title: MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells.
abstract: Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here, we provide evidence that MLL-ENL also inhibits Polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as a scaffold that contacted the elongation machinery as well as the Polycomb repressive complex 1 (PRC1) component CBX8. These interactions were mutually exclusive in vitro, corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay, and this effect was neutralized by direct association with ENL. Correspondingly, CBX8-binding-defective MLL-ENL could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as a neomorphic activity that may augment Polycomb inhibition and transformation.
authors.affiliation: Department of Genetics, University Erlangen, 91058 Erlangen, Germany.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Maethner
authors.forename: Maria-Paz
authors.initials: MP
authors.lastname: Garcia-Cuellar
authors.forename: Constanze
authors.initials: C
authors.lastname: Breitinger
authors.forename: Sylvia
authors.initials: S
authors.lastname: Takacova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Divoky
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
authors.forename: Robert K
authors.initials: RK
authors.lastname: Slany
mesh_terms: D002471:Cell Transformation, Neoplastic; D019281:Dimerization; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C570428:CBX8 protein, human; C090862:ELL protein, human; C497422:KMT2A protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D035602:Transcriptional Elongation Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D063150:Polycomb Repressive Complex 1