title: MicroRNA-486-5p is an erythroid oncomiR of the myeloid leukemias of Down syndrome.
abstract: Children with Down syndrome (DS) are at increased risk for acute myeloid leukemias (ML-DS) characterized by mixed megakaryocytic and erythroid phenotype and by acquired mutations in the GATA1 gene resulting in a short GATA1s isoform. The chromosome 21 microRNA (miR)-125b cluster has been previously shown to cooperate with GATA1s in transformation of fetal hematopoietic progenitors. In this study, we report that the expression of miR-486-5p is increased in ML-DS compared with non-DS acute megakaryocytic leukemias (AMKLs). miR-486-5p is regulated by GATA1 and GATA1s that bind to the promoter of its host gene ANK1. miR-486-5p is highly expressed in mouse erythroid precursors and knockdown (KD) in ML-DS cells reduced their erythroid phenotype. Ectopic expression and KD of miR-486-5p in primary fetal liver hematopoietic progenitors demonstrated that miR-486-5p cooperates with Gata1s to enhance their self renewal. Consistent with its activation of AKT, overexpression and KD experiments showed its importance for growth and survival of human leukemic cells. Thus, miR-486-5p cooperates with GATA1s in supporting the growth and survival, and the aberrant erythroid phenotype of the megakaryocytic leukemias of DS.
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel; Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel;
authors.forename: Lital
authors.initials: L
authors.lastname: Shaham
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
authors.forename: Elena
authors.initials: E
authors.lastname: Vendramini
authors.affiliation: Department of Oncology, Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI;
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Rosetta Genomics Ltd, Rehovot, Israel;
authors.forename: Yaron
authors.initials: Y
authors.lastname: Goren
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel;
authors.forename: Yehudit
authors.initials: Y
authors.lastname: Birger
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Marloes R
authors.initials: MR
authors.lastname: Tijssen
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL;
authors.forename: Maureen
authors.initials: M
authors.lastname: McNulty
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
authors.forename: Ifat
authors.initials: I
authors.lastname: Geron
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
authors.forename: Omer
authors.initials: O
authors.lastname: Schwartzman
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel;
authors.forename: Liat
authors.initials: L
authors.lastname: Goldberg
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Stella T
authors.initials: ST
authors.lastname: Chou
authors.affiliation: Department of Oncology, Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI;
authors.forename: Holly
authors.initials: H
authors.lastname: Pitman
authors.affiliation: Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel; Institute of Nanotechnology & Advanced Materials, Bar-Ilan University, Ramat-Gan, Israel; and.
authors.forename: Shulamit
authors.initials: S
authors.lastname: Michaeli
authors.affiliation: Department of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel;
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sredni
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.affiliation: Division of Hematology/Oncology, Northwestern University, Chicago, IL;
authors.forename: John D
authors.initials: JD
authors.lastname: Crispino
authors.affiliation: Department of Oncology, Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI; Division of Pediatric Hematology and Oncology, Children's Hospital of Michigan, Detroit, MI.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.affiliation: Childhood Leukemia Research Institute, Cancer Research Center, Sheba Medical Center, Ramat-Gan, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel;
authors.forename: Shai
authors.initials: S
authors.lastname: Izraeli
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002675:Child, Preschool; D004314:Down Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D041905:Erythroid Cells / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D008533:Megakaryocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs