title: A tumorigenic MLL-homeobox network in human glioblastoma stem cells.
abstract: Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL-Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non-tumor-initiating cells in glioblastoma.
authors.affiliation: Program in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada.
authors.forename: Marco
authors.initials: M
authors.lastname: Gallo
authors.forename: Jenny
authors.initials: J
authors.lastname: Ho
authors.forename: Fiona J
authors.initials: FJ
authors.lastname: Coutinho
authors.forename: Robert
authors.initials: R
authors.lastname: Vanner
authors.forename: Lilian
authors.initials: L
authors.lastname: Lee
authors.forename: Renee
authors.initials: R
authors.lastname: Head
authors.forename: Erick K M
authors.initials: EK
authors.lastname: Ling
authors.forename: Ian D
authors.initials: ID
authors.lastname: Clarke
authors.forename: Peter B
authors.initials: PB
authors.lastname: Dirks
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D005801:Genes, Homeobox / Q000502:physiology*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase