Olfactomedin 4 is a novel target gene of retinoic acids and 5-aza-2 '-deoxycytidine involved in human myeloid leukemia cell growth, differentiation, and apoptosis

Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blood (Impact Factor: 10.45). 12/2010; 116(23):4938-47. DOI: 10.1182/blood-2009-10-246439
Source: PubMed


Clinical application of retinoic acids (RAs) and demethylation agents has proven to be effective in treating certain myeloid leukemia patients. However, the target genes that mediate these antileukemia activities are still poorly understood. In this study, we identified olfactomedin 4 (OLFM4), a myeloid-lineage-specific gene from the olfactomedin family, as a novel target gene for RAs and the demethylation agent, 5-aza-2'-deoxycytidine. We demonstrated that the retinoic acid receptor alpha/retinoic X receptor alpha heterodimer binds to a retinoic acid response-element (DR5) site in the OLFM4 promoter and mediates all-trans-retinoic acid (ATRA)-induced transactivation of the OLFM4 gene. OLFM4 overexpression in HL-60 cells led to growth inhibition, differentiation, and apoptosis, and potentiated ATRA induction of these effects. Conversely, down-regulation of endogenous OLFM4 in acute myeloid leukemia-193 cells compromised ATRA-induced growth inhibition, differentiation, and apoptosis. Overexpression of OLFM4 in HL-60 cells inhibited constitutive and ATRA-induced phosphorylation of the eukaryote initiation factor 4E-binding protein 1 (4E-BP1), whereas down-regulation of OLFM4 protein in acute myeloid leukemia-193 cells increased 4E-BP1 phosphorylation, suggesting that OLFM4 is a potent upstream inhibitor of 4E-BP1 phosphorylation/deactivation. Thus, our study demonstrates that OLFM4 plays an important role in myeloid leukemia cellular functions and induction of OLFM4-mediated effects may contribute to the therapeutic value of ATRA.

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    • "The H3K27ac mark is present at this enhancer in LGR5 + stem cells but lost after differentiation. Previously, DNA methylation had also been correlated with OLFM4 expression in human cancer, and the proximal DMR we identified in the mouse Olfm4 gene contains six of the eight corresponding CpGs of the human promoter that are important for cancer-induced expression through retinoic acid signaling (Liu et al. 2010). "
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    Genes & development 03/2014; 28(6):652-64. DOI:10.1101/gad.230318.113 · 10.80 Impact Factor
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    • "Olfactomedin 4 (OLFM4) is a member of the olfactomedin-related glycoprotein family, which is specifically expressed in neutrophils and the gastrointestinal tract [29], [30]. It plays an important role in myeloid leukemia cellular functions [31] and may be a novel target gene for retinoic acids and the demethylation agent, 5-aza-2′-deoxycytidine [31]. Most recently, by analyzing the expression of OLFM4 mRNA in myeloid cells from normal human bone marrow, it has been demonstrated that OLFM4 mRNA is a genuine constituent of neutrophil specific granules [32]. "
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    • "The current clinical trials for leukemia include the pharmaceutical medications, debilitating radiation, and a bone marrow transplant therapy but these strategies have not proven to be satisfied. Hence, new targets for treating leukemia are necessary and the best functions for agents are carried out through promoting differentiation or trigging apoptotic death in leukemia cells [7], [8]. Apoptosis, a process of programmed cell death type I, is a major method of anticancer properties to eliminate cancer cells [9]. "
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