Regulation of vitamin D receptor expression by retinoic acid receptor alpha in acute myeloid leukemia cells

Geoffrey Brown, Aleksandra Marchwicka, Małgorzata Cebrat, Agnieszka Łaszkiewicz, Łukasz Śnieżewski, Ewa Marcinkowska

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14 Citations (Scopus)
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Abstract

Acute myeloid leukemia (AML) is the predominant acute leukemia among adults, characterized by an accumulation of malignant immature myeloid precursors. A very promising way to treat AML is differentiation therapy using either all-trans-retinoic acid (ATRA) or 1,25-dihydroxyvitamin D3 (1,25D), or the use of both these differentiation-inducing agents. However, the effect of combination treatment varies in different AML cell lines, and this is due to ATRA either down- or up-regulating transcription of vitamin D receptor (VDR) in the cells examined. The mechanism of transcriptional regulation of VDR in response to ATRA has not been fully elucidated. Here, we show that the retinoic acid receptor α (RARα) is responsible for regulating VDR transcription in AML cells. We have shown that a VDR transcriptional variant, originating in exon 1a, is regulated by RARα agonists in AML cells. Moreover, in cells with a high basal level of RARα protein, the VDR gene is transcriptionally repressed as long as RARα agonist is absent. In these cells down-regulation of the level of RARα leads to increased expression of VDR. We consider that our findings provide a mechanistic background to explain the different outcomes from treating AML cell lines with a combination of ATRA and 1,25D.
Original languageEnglish
JournalThe Journal of Steroid Biochemistry and Molecular Biology
Early online date8 Mar 2016
DOIs
Publication statusE-pub ahead of print - 8 Mar 2016

Keywords

  • Vitamin D receptor
  • Retinoic acid receptor alpha
  • Expression
  • mRNA
  • Target gene
  • Differentiation

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