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

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. GinzburgHughes de Thé, Marc Benhamou, Renato C. Monteiro, George S. Vassiliou, Olivier Hermine, Ivan C. Moura

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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.

Original language	English
Pages (from-to)	739-754.e4
Journal	Cell Reports
Volume	30
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2019.12.055
State	Published - 21 Jan 2020
Externally published	Yes

Keywords

acute myeloid leukemia
leukemic stem cell
vitamin D receptor

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10.1016/j.celrep.2019.12.055

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Paubelle, E., Zylbersztejn, F., Maciel, T. T., Carvalho, C., Mupo, A., Cheok, M., Lieben, L., Sujobert, P., Decroocq, J., Yokoyama, A., Asnafi, V., Macintyre, E., Tamburini, J., Bardet, V., Castaigne, S., Preudhomme, C., Dombret, H., Carmeliet, G., Bouscary, D., ... Moura, I. C. (2020). Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow. Cell Reports, 30(3), 739-754.e4. https://doi.org/10.1016/j.celrep.2019.12.055

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title = "Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow",

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",

author = "Etienne Paubelle and Florence Zylbersztejn and Maciel, {Thiago Trovati} and Caroline Carvalho and Annalisa Mupo and Meyling Cheok and Liesbet Lieben and Pierre Sujobert and Justine Decroocq and Akihiko Yokoyama and Vahid Asnafi and Elizabeth Macintyre and J{\'e}r{\^o}me Tamburini and Val{\'e}rie Bardet and Sylvie Castaigne and Claude Preudhomme and Herv{\'e} Dombret and Geert Carmeliet and Didier Bouscary and Ginzburg, {Yelena Z.} and {de Th{\'e}}, Hughes and Marc Benhamou and Monteiro, {Renato C.} and Vassiliou, {George S.} and Olivier Hermine and Moura, {Ivan C.}",

note = "Publisher Copyright: {\textcopyright} 2019",

year = "2020",

month = jan,

day = "21",

doi = "10.1016/j.celrep.2019.12.055",

language = "English",

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Paubelle, E, Zylbersztejn, F, Maciel, TT, Carvalho, C, Mupo, A, Cheok, M, Lieben, L, Sujobert, P, Decroocq, J, Yokoyama, A, Asnafi, V, Macintyre, E, Tamburini, J, Bardet, V, Castaigne, S, Preudhomme, C, Dombret, H, Carmeliet, G, Bouscary, D, Ginzburg, YZ, de Thé, H, Benhamou, M, Monteiro, RC, Vassiliou, GS, Hermine, O & Moura, IC 2020, 'Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow', Cell Reports, vol. 30, no. 3, pp. 739-754.e4. https://doi.org/10.1016/j.celrep.2019.12.055

TY - JOUR

T1 - Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow

AU - Paubelle, Etienne

AU - Zylbersztejn, Florence

AU - Maciel, Thiago Trovati

AU - Carvalho, Caroline

AU - Mupo, Annalisa

AU - Cheok, Meyling

AU - Lieben, Liesbet

AU - Sujobert, Pierre

AU - Decroocq, Justine

AU - Yokoyama, Akihiko

AU - Asnafi, Vahid

AU - Macintyre, Elizabeth

AU - Tamburini, Jérôme

AU - Bardet, Valérie

AU - Castaigne, Sylvie

AU - Preudhomme, Claude

AU - Dombret, Hervé

AU - Carmeliet, Geert

AU - Bouscary, Didier

AU - Ginzburg, Yelena Z.

AU - de Thé, Hughes

AU - Benhamou, Marc

AU - Monteiro, Renato C.

AU - Vassiliou, George S.

AU - Hermine, Olivier

AU - Moura, Ivan C.

PY - 2020/1/21

Y1 - 2020/1/21

N2 - 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.

AB - 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.

KW - acute myeloid leukemia

KW - leukemic stem cell

KW - vitamin D receptor

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U2 - 10.1016/j.celrep.2019.12.055

DO - 10.1016/j.celrep.2019.12.055

M3 - Article

C2 - 31968250

AN - SCOPUS:85077971916

SN - 2211-1247

VL - 30

SP - 739-754.e4

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

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Keywords

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