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    Cell stem cell. pii: S1934-5909(19)30299-1. doi: 10.1016/j.stem.2019.07.001
    Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.
    McKenzie MD1,  Ghisi M2,  Oxley EP3,  Ngo S4,  Cimmino L5,  Esnault C6,  Liu R7,  Salmon JM8,  Bell CC9,  Ahmed N10,  Erlichster M11,  Witkowski MT12,  Liu GJ13,  Chopin M14,  Dakic A15,  Simankowicz E16,  Pomilio G17,  Vu T18,  Krsmanovic P19,  Su S20,  Tian L21,  Baldwin TM22,  Zalcenstein DA23,  DiRago L24,  Wang S25,  Metcalf D26,  Johnstone RW27,  Croker BA28,  Lancaster GI29,  Murphy AJ30,  Naik SH31,  Nutt SL32,  Pospisil V33,  Schroeder T34,  Wall M35,  Dawson MA36,  Wei AH37,  de Thé H38,  Ritchie ME39,  Zuber J40,  Dickins RA41
    Author information
    1Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    2Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    3Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    4Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    5Department of Pathology, New York University School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
    6Collège de France, PSL Research University, 75005 Paris, France; INSERM U944, CNRS UMR7212, Université de Paris, Institut de Recherche Saint Louis, 75010 Paris, France; Assistance Publique/Hôpitaux de Paris, Oncologie Moléculaire, Hôpital St. Louis, 75010 Paris, France.
    7Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    8Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    9Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
    10Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
    11Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
    12Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia; Department of Pathology, New York University School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
    13Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
    14Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    15Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    16Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    17Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia; Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
    18Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    19Institute of Pathological Physiology and Biocev, First Faculty of Medicine, Charles University, Prague, Czech Republic.
    20Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    21Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
    22Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    23Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    24Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    25Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
    26Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    27Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
    28Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
    29Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Immunology and Pathology, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    30Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Immunology and Pathology, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
    31Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia.
    32Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
    33Institute of Pathological Physiology and Biocev, First Faculty of Medicine, Charles University, Prague, Czech Republic.
    34Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
    35Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Victorian Cancer Cytogenetics Service, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065, Australia.
    36Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
    37Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia; Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
    38Collège de France, PSL Research University, 75005 Paris, France; INSERM U944, CNRS UMR7212, Université de Paris, Institut de Recherche Saint Louis, 75010 Paris, France; Assistance Publique/Hôpitaux de Paris, Oncologie Moléculaire, Hôpital St. Louis, 75010 Paris, France.
    39Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; School of Mathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia.
    40Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, 1030 Vienna, Austria; Medical University of Vienna, 1030 Vienna, Austria.
    41Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia. Electronic address: ross.dickins@monash.edu.
    Abstract

    Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The clinical success of these approaches depends on CSC differentiation being unidirectional rather than reversible, yet this question remains unresolved even in prototypically hierarchical malignancies, such as acute myeloid leukemia (AML). Here, we show in murine and human models of AML that, upon perturbation of endogenous expression of the lineage-determining transcription factor PU.1 or withdrawal of established differentiation therapies, some mature leukemia cells can de-differentiate and reacquire clonogenic and leukemogenic properties. Our results reveal plasticity of CSC maturation in AML, highlighting the need to therapeutically eradicate cancer cells across a range of differentiation states.


    Copyright © 2019 Elsevier Inc. All rights reserved.

    KEYWORDS: PU.1, acute myeloid leukemia, acute promyelocytic leukemia, cancer stem cell, differentiation therapy, leukemia stem cell, myelopoiesis, pioneer factor, retinoic acid, transcription factor

    Publikations ID: 31374198
    Quelle: öffnen
     
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