title: β-Catenin mediates the establishment and drug resistance of MLL leukemic stem cells.
abstract: Identification of molecular pathways essential for cancer stem cells is critical for understanding the underlying biology and designing effective cancer therapeutics. Here, we demonstrated that β-catenin was activated during development of MLL leukemic stem cells (LSCs). Suppression of β-catenin reversed LSCs to a pre-LSC-like stage and significantly reduced the growth of human MLL leukemic cells. Conditional deletion of β-catenin completely abolished the oncogenic potential of MLL-transformed cells. In addition, established MLL LSCs that have acquired resistance against GSK3 inhibitors could be resensitized by suppression of β-catenin expression. These results unveil previously unrecognized multifaceted functions of β-catenin in the establishment and drug-resistant properties of MLL stem cells, highlighting it as a potential therapeutic target for an important subset of AMLs.
authors.affiliation: Department of Haematological Medicine, King's College London, Denmark Hill, UK.
authors.forename: Jenny
authors.initials: J
authors.lastname: Yeung
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Esposito
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gandillet
authors.forename: Bernd B
authors.initials: BB
authors.lastname: Zeisig
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Griessinger
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: Chi Wai Eric
authors.initials: CW
authors.lastname: So
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D051153:Wnt Proteins / Q000502:physiology; D051176:beta Catenin / Q000502:physiology*
chemical_list: C497422:KMT2A protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; D038362:Glycogen Synthase Kinase 3