Resistance to 1,25D-induced differentiation in human acute myeloid leukemia HL60-40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor

Plant polyphenols have been shown to enhance the differentiation of acute myeloid leukemia (AML) cells induced by the hormonal form of vitamin D3 (1α,25-dihydroxyvitamin D3; 1,25D). However, how these agents modulate 1,25D effects in different subtypes of AML cells remains poorly understood. Here, we show that both carnosic acid (CA) and silibinin (SIL) synergistically enhancd 1,25D-induced differentiation of myeloblastic HL60 cells. However, in promonocytic U937 cells, only CA caused potentiation while SIL attenuated 1,25D effect. The enhanced effect of 1,25D+CA was accompanied by increases in both the vitamin D receptor (VDR) and retinoid X receptor alpha (RXRα) protein levels and vitamin D response element (VDRE) transactivation in both cell lines. Similar increases were observed in HL60 cells treated with 1,25D + SIL. In U937 cells, however, SIL inhibited 1,25D-induced VDRE transactivation concomitant with downregulation of RXRα at both transcriptional and posttranscriptional levels. These inhibitory effects correlated with the inability of SIL, with or without 1,25D, to activate the Nrf2/antioxidant response element signaling pathway in U937 cells. These results suggest that opposite effects of SIL on 1,25D-induced differentiation of HL60 and U937 cells may be determined by cell-type-specific signaling and transcriptional responses to this polyphenol resulting in differential modulation of RXRα expression.

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FLT3 regulates β-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells

Leukemia ◽

10.1038/sj.leu.2404923 ◽

2007 ◽

Vol 21 (12) ◽

pp. 2476-2484 ◽

Cited By ~ 25

Author(s):

T Kajiguchi ◽

E J Chung ◽

S Lee ◽

A Stine ◽

H Kiyoi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Tyrosine Phosphorylation ◽

Nuclear Localization ◽

Myeloid Leukemia ◽

Transcriptional Activity ◽

Leukemia Cells ◽

Acute Myeloid Leukemia Cells ◽

Acute Myeloid

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Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations

Cancers ◽

10.3390/cancers13205243 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5243

Author(s):

Marie Sabatier ◽

Emeline Boet ◽

Sonia Zaghdoudi ◽

Nathan Guiraud ◽

Alexis Hucteau ◽

...

Keyword(s):

Vitamin D ◽

Acute Myeloid Leukemia ◽

Vitamin D Receptor ◽

Myeloid Leukemia ◽

Dependent Manner ◽

Cooperative Effects ◽

Idh Mutations ◽

Transcriptional Changes ◽

Acute Myeloid

Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.

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