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

doi:10.1016/j.celrep.2019.12.055

Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow

Cell Rep. 2020 Jan 21;30(3):739-754.e4. doi: 10.1016/j.celrep.2019.12.055.

Authors

Etienne Paubelle¹, Florence Zylbersztejn², Thiago Trovati Maciel³, Caroline Carvalho³, Annalisa Mupo⁴, Meyling Cheok⁵, Liesbet Lieben⁶, Pierre Sujobert⁷, Justine Decroocq², Akihiko Yokoyama⁸, Vahid Asnafi⁹, Elizabeth Macintyre⁹, Jérôme Tamburini⁷, Valérie Bardet², Sylvie Castaigne¹⁰, Claude Preudhomme⁵, Hervé Dombret¹¹, Geert Carmeliet⁶, Didier Bouscary⁷, Yelena Z Ginzburg¹², Hughes de Thé¹³, Marc Benhamou¹⁴, Renato C Monteiro¹⁴, George S Vassiliou⁴, Olivier Hermine¹⁵, Ivan C Moura¹⁶

Affiliations

¹ 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. Electronic address: paubelle-e@chu-caen.fr.
² 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.
³ INSERM UMR 1163, Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, 75015 Paris, France.
⁴ Haematological Cancer Genetics, Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Hinxton Cambridge CB10 1SA, UK.
⁵ Centre of Research Jean-Pierre Aubert, INSERM UMR 837, 59000 Lille, France.
⁶ Laboratory of Experimental Medicine and Endocrinology, KU Leuven 3000, Belgium.
⁷ 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.
⁸ National Cancer Center Research Institute, Chiba 277-8577, Japan.
⁹ Department of Biological Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker, 75015 Paris, France.
¹⁰ Department of Hematology, Hôpital Mignot, 78150 Le Chesnay, France.
¹¹ Department of Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, 75010 Paris, France.
¹² Erythropoiesis Laboratory, LFKRI, New York Blood Center, New York, NY, USA.
¹³ Molecular Virology and Pathology, INSERM UMR 944, 75010 Paris, France; Molecular Virology and Pathology, CNRS 7212, 75010 Paris, France.
¹⁴ INSERM U1149, Center for Research on Inflammation, 75018 Paris, France.
¹⁵ 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. Electronic address: ohermine@gmail.com.
¹⁶ 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.

PMID: 31968250
DOI: 10.1016/j.celrep.2019.12.055

Abstract

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.

Keywords: acute myeloid leukemia; leukemic stem cell; vitamin D receptor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Azacitidine / pharmacology
Bone Marrow / drug effects
Bone Marrow / pathology*
Cell Count
Cell Cycle / drug effects
Cell Differentiation / drug effects
Cell Line, Tumor
DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors
DNA (Cytosine-5-)-Methyltransferases / metabolism
DNA Methylation / genetics
Disease Progression
Female
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / drug effects
Humans
Leukemia, Myeloid, Acute / metabolism*
Leukemia, Myeloid, Acute / pathology*
Mice, Inbred C57BL
Monocytes / drug effects
Monocytes / pathology
Myeloid Cells / drug effects
Myeloid Cells / metabolism
Myeloid Cells / pathology
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology*
Oncogenes
Promoter Regions, Genetic / genetics
Receptors, Calcitriol / metabolism*
Signal Transduction / drug effects
Survival Analysis
Tumor Stem Cell Assay

Substances

Receptors, Calcitriol
DNA (Cytosine-5-)-Methyltransferases
Azacitidine

Abstract

Publication types

MeSH terms

Substances

Grants and funding