title: miR-126 Regulates Distinct Self-Renewal Outcomes in Normal and Malignant Hematopoietic Stem Cells.
abstract: To investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lechman
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Hospital, Milan 20132, Italy; Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy; Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital, Milan 20132, Italy.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Gentner
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 2M9, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Stanley W K
authors.initials: SW
authors.lastname: Ng
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Schoof
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: van Galen
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: James A
authors.initials: JA
authors.lastname: Kennedy
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Hospital, Milan 20132, Italy; Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Nucera
authors.affiliation: Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy; Hematology and Bone Marrow Transplantation Unit, San Raffaele Hospital, Milan 20132, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ciceri
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Kerstin B
authors.initials: KB
authors.lastname: Kaufmann
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Naoya
authors.initials: N
authors.lastname: Takayama
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Dobson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Aaron
authors.initials: A
authors.lastname: Trotman-Grant
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Krivdova
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Janneke
authors.initials: J
authors.lastname: Elzinga
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mitchell
authors.affiliation: Department of Hematology and Transfusion Medicine, Lund University Hospital, Lund 221 84, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Karin G
authors.initials: KG
authors.lastname: Hermans
authors.affiliation: Department of Pediatrics, McGill University and The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
authors.forename: Kolja
authors.initials: K
authors.lastname: Eppert
authors.affiliation: Laboratory of Pediatric Oncology, Radboud University Medical Center, Nijmegen, 6500 HB, Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Marke
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Isserlin
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Veronique
authors.initials: V
authors.lastname: Voisin
authors.affiliation: The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 2M9, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Yale Stem Cell Center, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Minden
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Medicine, University of Toronto, Toronto, ON M5G 2M9, Canada.
authors.forename: Jean C Y
authors.initials: JC
authors.lastname: Wang
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy, San Raffaele Hospital, Milan 20132, Italy; Vita Salute San Raffaele University, San Raffaele Scientific Institute, San Raffaele Hospital, Milan 20132, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Naldini
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada; Princess Margaret Cancer Research Tower, Room 8-301, 101 College Street, Toronto M5G 1L7, Canada. Electronic address: jdick@uhnresearch.ca.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C527111:MIRN126 microRNA, human; C546842:MTOR protein, human
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