title: Genetically distinct leukemic stem cells in human CD34- acute myeloid leukemia are arrested at a hemopoietic precursor-like stage.
abstract: Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34(-), there are multiple, nonhierarchically arranged CD34(+) and CD34(-) LSC populations. Within CD34(-) and CD34(+) LSC-containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34(-) LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34(-) mature granulocyte-macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis.
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: Quek
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Georg W
authors.identifier: 0000-0002-3929-948X
authors.initials: GW
authors.lastname: Otto
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Garnett
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Ludovic
authors.identifier: 0000-0003-2498-0376
authors.initials: L
authors.lastname: Lhermitte
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Karamitros
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Bilyana
authors.initials: B
authors.lastname: Stoilova
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: I-Jun
authors.identifier: 0000-0003-1727-3243
authors.initials: IJ
authors.lastname: Lau
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Jessica
authors.initials: J
authors.lastname: Doondeea
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Batchimeg
authors.identifier: 0000-0001-5914-3848
authors.initials: B
authors.lastname: Usukhbayar
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Kennedy
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Marlen
authors.initials: M
authors.lastname: Metzner
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Nicolas
authors.identifier: 0000-0002-5093-0922
authors.initials: N
authors.lastname: Goardon
authors.affiliation: Department of Genetics, King's College London, London WC2R 2LS, England, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Ivey
authors.affiliation: Cancer Institute, University College London, London WC1E 6BT, England, UK.
authors.forename: Christopher
authors.identifier: 0000-0002-5310-0529
authors.initials: C
authors.lastname: Allen
authors.affiliation: Cancer Institute, University College London, London WC1E 6BT, England, UK.
authors.forename: Rosemary
authors.identifier: 0000-0002-0103-1787
authors.initials: R
authors.lastname: Gale
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Benjamin
authors.identifier: 0000-0002-4878-0697
authors.initials: B
authors.lastname: Davies
authors.affiliation: Department of Hematology, Great Western Hospital National Health Service Foundation Trust, Swindon SN3 6BB, England, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sternberg
authors.affiliation: Department of Hematology, Royal Bournemouth and Christchurch Hospital National Health Service Trust, Bournemouth BH7 7DW, England, UK.
authors.forename: Sally
authors.identifier: 0000-0002-7769-1562
authors.initials: S
authors.lastname: Killick
authors.affiliation: Department of Hematology, Plymouth Hospitals National Health Service Trust, Plymouth PL6 8DH, England, UK.
authors.forename: Hannah
authors.initials: H
authors.lastname: Hunter
authors.affiliation: Department of Hematology, Blackpool, Fylde and Wyre Hospitals National Health Service Trust, Blackpool FY3 8NR, England, UK.
authors.forename: Paul
authors.identifier: 0000-0001-7358-2396
authors.initials: P
authors.lastname: Cahalin
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Price
authors.affiliation: Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Andrew
authors.identifier: 0000-0001-5940-1464
authors.initials: A
authors.lastname: Carr
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham B15 2TG, England, UK.
authors.forename: Mike
authors.identifier: 0000-0001-5112-2882
authors.initials: M
authors.lastname: Griffiths
authors.affiliation: Department of Immunology, North Bristol National Health Service Trust, Bristol BS10 5NB, England, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Virgo
authors.affiliation: Cancer Institute, University College London, London WC1E 6BT, England, UK Department of Hematology, University College London Hospital National Health Service Foundation Trust, London NW1 2BU, England, UK.
authors.forename: Stephen
authors.identifier: 0000-0002-6289-4295
authors.initials: S
authors.lastname: Mackinnon
authors.affiliation: Department of Genetics, King's College London, London WC2R 2LS, England, UK.
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham B15 2TT, England, UK Department of Haematology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, England, UK.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Freeman
authors.affiliation: Centre for Clinical Hematology, Nottingham University Hospitals National Health Service Trust, Nottingham NG5 1PB, England, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Russell
authors.affiliation: Department of Clinical Haematology, University of Birmingham, Birmingham B15 2TT, England, UK Department of Clinical Haematology, University Hospitals Birmingham National Health Service Foundation Trust, Birmingham B15 2TH, England, UK.
authors.forename: Charles
authors.identifier: 0000-0001-5041-6678
authors.initials: C
authors.lastname: Craddock
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Mead
authors.affiliation: Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK.
authors.forename: Andrew
authors.identifier: 0000-0002-6833-9882
authors.initials: A
authors.lastname: Peniket
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK.
authors.forename: Catherine
authors.identifier: 0000-0002-9015-5203
authors.initials: C
authors.lastname: Porcher
authors.affiliation: Medical Research Council, Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX1 2JD, England, UK Department of Hematology, Oxford University Hospital National Health Service Trust, Oxford OX3 9DU, England, UK paresh.vyas@imm.ox.ac.uk.
authors.forename: Paresh
authors.identifier: 0000-0003-3931-0914
authors.initials: P
authors.lastname: Vyas
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics* / Q000378:metabolism; D055014:Granulocyte-Macrophage Progenitor Cells / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D018952:Antigens, CD34; D009363:Neoplasm Proteins