Cell Reports (Jan 2020)
Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow
- Etienne Paubelle,
- Florence Zylbersztejn,
- Thiago Trovati Maciel,
- Caroline Carvalho,
- Annalisa Mupo,
- Meyling Cheok,
- Liesbet Lieben,
- Pierre Sujobert,
- Justine Decroocq,
- Akihiko Yokoyama,
- Vahid Asnafi,
- Elizabeth Macintyre,
- Jérôme Tamburini,
- Valérie Bardet,
- Sylvie Castaigne,
- Claude Preudhomme,
- Hervé Dombret,
- Geert Carmeliet,
- Didier Bouscary,
- Yelena Z. Ginzburg,
- Hughes de Thé,
- Marc Benhamou,
- Renato C. Monteiro,
- George S. Vassiliou,
- Olivier Hermine,
- Ivan C. Moura
Affiliations
- Etienne Paubelle
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Department of Clinical Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France; Corresponding author
- Florence Zylbersztejn
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France
- Thiago Trovati Maciel
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France
- Caroline Carvalho
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France
- Annalisa Mupo
- Haematological Cancer Genetics, Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton Cambridge CB10 1SA, UK
- Meyling Cheok
- Centre of Research Jean-Pierre Aubert, INSERM UMR 837, 59000 Lille, France
- Liesbet Lieben
- Laboratory of Experimental Medicine and Endocrinology, KU Leuven 3000, Belgium
- Pierre Sujobert
- Institut Cochin, Département d’Immuno-Hématologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, INSERM U1016 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France
- Justine Decroocq
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France
- Akihiko Yokoyama
- National Cancer Center Research Institute, Chiba 277-8577, Japan
- Vahid Asnafi
- Department of Biological Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France
- Elizabeth Macintyre
- Department of Biological Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France
- Jérôme Tamburini
- Institut Cochin, Département d’Immuno-Hématologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, INSERM U1016 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France
- Valérie Bardet
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France
- Sylvie Castaigne
- Department of Hematology, Hôpital Mignot, 78150 Le Chesnay, France
- Claude Preudhomme
- Centre of Research Jean-Pierre Aubert, INSERM UMR 837, 59000 Lille, France
- Hervé Dombret
- Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France
- Geert Carmeliet
- Laboratory of Experimental Medicine and Endocrinology, KU Leuven 3000, Belgium
- Didier Bouscary
- Institut Cochin, Département d’Immuno-Hématologie, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 8104, INSERM U1016 Paris, France; Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité, Paris, France; Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France
- Yelena Z. Ginzburg
- Erythropoiesis Laboratory, LFKRI, New York Blood Center, New York, NY, USA
- Hughes de Thé
- Molecular Virology and Pathology, INSERM UMR 944, 75010 Paris, France; Molecular Virology and Pathology, CNRS 7212, 75010 Paris, France
- Marc Benhamou
- INSERM U1149, Center for Research on Inflammation, 75018 Paris, France
- Renato C. Monteiro
- INSERM U1149, Center for Research on Inflammation, 75018 Paris, France
- George S. Vassiliou
- Haematological Cancer Genetics, Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton Cambridge CB10 1SA, UK
- Olivier Hermine
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Department of Clinical Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France; Laboratory of Excellence GR-Ex, 75015 Paris, France; Corresponding author
- Ivan C. Moura
- INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Paris Descartes – Sorbonne Paris Cité University, Imagine Institute, 75015 Paris, France; CNRS ERL 8254, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France; Laboratory of Excellence GR-Ex, 75015 Paris, France
- Journal volume & issue
-
Vol. 30,
no. 3
pp. 739 – 754.e4
Abstract
Summary: Vitamin D (VD) is a known differentiating agent, but the role of VD receptor (VDR) is still incompletely described in acute myeloid leukemia (AML), whose treatment is based mostly on antimitotic chemotherapy. Here, we present an unexpected role of VDR in normal hematopoiesis and in leukemogenesis. Limited VDR expression is associated with impaired myeloid progenitor differentiation and is a new prognostic factor in AML. In mice, the lack of Vdr results in increased numbers of hematopoietic and leukemia stem cells and quiescent hematopoietic stem cells. In addition, malignant transformation of Vdr−/− cells results in myeloid differentiation block and increases self-renewal. Vdr promoter is methylated in AML as in CD34+ cells, and demethylating agents induce VDR expression. Association of VDR agonists with hypomethylating agents promotes leukemia stem cell exhaustion and decreases tumor burden in AML mouse models. Thus, Vdr functions as a regulator of stem cell homeostasis and leukemic propagation. : Paubelle et al. show that targeting the vitamin D receptor has anti-leukemic activity by acting on cell differentiation and by decreasing stemness of AML cells. Keywords: acute myeloid leukemia, vitamin D receptor, leukemic stem cell
