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Cell Stem Cell. 2019 Aug 1;25(2):258-272.e9. doi: 10.1016/j.stem.2019.07.001.

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.

Author information

1
Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
2
Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
3
Department of Pathology, New York University School of Medicine, 550 1(st) Avenue, New York, NY 10016, USA.
4
Collège 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.
5
Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3010, Australia.
6
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
7
Molecular 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.
8
Molecular 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.
9
Molecular 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.
10
Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
11
Australian Centre for Blood Diseases, Monash University, Commercial Road, Melbourne, VIC 3004, Australia; Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
12
Institute of Pathological Physiology and Biocev, First Faculty of Medicine, Charles University, Prague, Czech Republic.
13
Cancer and Haematology Division, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3052, Australia.
14
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
15
Department 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.
16
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
17
Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Immunology and Pathology, Monash University, Commercial Road, Melbourne, VIC 3004, Australia.
18
Department 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.
19
Department 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.
20
Molecular 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.
21
Research Institute of Molecular Pathology, Campus Vienna Biocenter 1, 1030 Vienna, Austria; Medical University of Vienna, 1030 Vienna, Austria.
22
Australian 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.

KEYWORDS:

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

PMID:
31374198
DOI:
10.1016/j.stem.2019.07.001

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