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

Paubelle, Étienne; Zylbersztejn, Florence; Maciel, Thiago; Carvalho, Caroline; Mupo, Annalisa; Cheok, Meyling; Lieben, Liesbet; Sujobert, Pierre; Decroocq, Justine; Yokoyama, Akihiko; Asnafi, Vahid; Macintyre, Elizabeth; Tamburini, Jérôme; Bardet, Valérie; Castaigné, Sylvie; Preudhomme, Claude; Dombret, Hervé; Carmeliet, Geert; Bouscary, Didier; Ginzburg, Yelena; The, H de; Benhamou, Marc; Monteiro, Renato C.; Vassiliou, George S.; Hermine, Olivier; Moura, Ivan C.

doi:10.1016/j.celrep.2019.12.055

Cited by 41 publications

(31 citation statements)

References 59 publications

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“…Clearly, any evidence for ATRA-reversible deregulation of retinoid signaling in other settings than APL could have considerable impact for patient care. Interestingly, some related findings were recently reported with vitD3 and its receptor [173]. Thus, links between nuclear receptor signaling and cancer is likely to be broader than the narrow example of APL and related APL-like diseases.…”

Section: Conclusion: Deregulated Retinoic Acid Signaling In Other Mamentioning

confidence: 74%

Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

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Most acute promyelocytic leukemia (APL) are caused by PML-RARA, a translocation-driven fusion oncoprotein discovered three decades ago. Over the years, several other types of rare X-RARA fusions have been described, while recently, oncogenic fusion proteins involving other retinoic acid receptors (RARB or RARG) have been associated to very rare cases of acute promyelocytic leukemia. PML-RARA driven pathogenesis and the molecular basis for therapy response have been the focus of many studies, which have now converged into an integrated physio-pathological model. The latter is well supported by clinical and molecular studies on patients, making APL one of the rare hematological disorder cured by targeted therapies. Here we review recent data on APL-like diseases not driven by the PML-RARA fusion and discuss these in view of current understanding of “classic” APL pathogenesis and therapy response.

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Section: Conclusion: Deregulated Retinoic Acid Signaling In Other Mamentioning

confidence: 74%

Classic and Variants APLs, as Viewed from a Therapy Response

Geoffroy

2020

Cancers

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“…Our finding is consistent with recent publication from Paubelle et al that VDR is important for myeloid progenitor differentiation and is a prognostic factor in AML. Further, mice with deficient VDR have increased numbers of hematopoietic and leukemia stem cells [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

A novel vitamin D gene therapy for acute myeloid leukemia

Payne

Pham

et al. 2020

Translational Oncology

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Current treatment approaches for older adult patients with acute myeloid leukemia (AML) are often toxic and lack efficacy. Active vitamin D3 (1,25(OH) 2 D3) has been shown to induce myeloid blast differentiation but at concentrations that have resulted in unacceptable, off-target hypercalcemia in clinical trials. In our study, we found that the combination of 1,25(OH) 2 D3 and the hypomethylating agent (HMA) 5-Azacytidine (AZA) enhanced cytotoxicity and differentiation, and inhibited proliferation of several AML cell lines (MOLM-14, HL60) and primary AML patient samples. This observation was corroborated by our RNA sequence analysis data in which VDR, CD14, and BAX expression were increased, and FLT-3, PIM1 and Bcl-2 expression were decreased. To address the hypercalcemia issue, we genetically engineered MOLM-14 cells to constantly express CYP27B1 (the VD3 activating enzyme, 1-α-hydroxylase-25(OH)D3) through lentiviral transduction procedures. Subsequently, we used these cells as vehicles to deliver the CYP27B1 enzyme to the bone marrow of AML mice. We observed that AML mice with CYP27B1 treatment had longer overall survival compared to no treatment and displayed no significant change in calcium level.

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“…The problem of the silencing of VDR gene expression has been addressed by the others with regard to blood cells. This year, a paper was published, which reported that VDR expression is partially regulated by methylation, and that combined hypomethylating drugs and VDR agonists synergistically induced AML cells' differentiation [32]. In this paper, the authors have presented their retrospective analysis of the AML cells from the GEO: GSE18700 study available in GenBank, which indicated that the promoter region of VDR in these cells was methylated.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Role of Methylation in Silencing of VDR Gene Expression in Normal Cells during Hematopoiesis and in Their Leukemic Counterparts

Nowak

Janik

Marchwicka

et al. 2020

Cells

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(1) Background: Vitamin D receptor (VDR) is present in multiple types of blood cells, and its ligand, 1,25-dihydroxyvitamin D (1,25D), is important for the proper functioning of the immune system. Activity of VDR is higher in hematopoietic stem and progenitor cells than in fully differentiated blood cells of mice and humans. In some human acute myeloid leukemia (AML) blasts, the expression of the VDR gene is also high. The mechanism of silencing the VDR gene expression during differentiation of blood cells has been addressed in this work. (2) Methods: The cells have been obtained using fluorescence activated sorting from murine tissues and from human umbilical cord blood (UCB). Then, the expression of the VDR gene and transcriptional activity of the VDR protein has been tested in real-time polymerase chain reaction (PCR). Eventually, the methylation of VDR promoter regions was tested using bisulfite sequencing. (3) Results: The CpG islands in VDR promoters were not methylated in the cells studied both in mice and in humans. The use of hypomethylating agents had no effect toward expression of human VDR transcripts, but it increased expression of the VDR-target gene, CYP24A1. (4) Conclusions: The expression of the VDR gene and transcriptional activity of the VDR protein varies at successive stages of hematopoietic differentiation in humans and mice, and in blasts from AML patients. The experiments presented in this case indicate that methylation of the promoter region of the VDR gene is not the major mechanism responsible for these differences.

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

Cited by 41 publications

References 59 publications

Classic and Variants APLs, as Viewed from a Therapy Response

Classic and Variants APLs, as Viewed from a Therapy Response

A novel vitamin D gene therapy for acute myeloid leukemia

Investigating the Role of Methylation in Silencing of VDR Gene Expression in Normal Cells during Hematopoiesis and in Their Leukemic Counterparts

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