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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Paubelle, Etienne 
Zylbersztejn, Florence 
Maciel, Thiago Trovati 
Carvalho, Caroline 

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.

Description

Keywords

acute myeloid leukemia, leukemic stem cell, vitamin D receptor, Animals, Apoptosis, Azacitidine, Bone Marrow, Cell Count, Cell Cycle, Cell Differentiation, Cell Line, Tumor, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Disease Progression, Female, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Mice, Inbred C57BL, Monocytes, Myeloid Cells, Neoplastic Stem Cells, Oncogenes, Promoter Regions, Genetic, Receptors, Calcitriol, Signal Transduction, Survival Analysis, Tumor Stem Cell Assay

Journal Title

Cell Rep

Conference Name

Journal ISSN

2211-1247
2211-1247

Volume Title

30

Publisher

Elsevier BV
Sponsorship
Medical Research Council (MC_PC_12009)
Medical Research Council (MC_PC_17230)
Cancer Research UK (23015)