Abstract
BackgroundAberrant CpG island methylation has been increasingly recognized as a common event in myelodysplastic syndrome (MDS). To date, most of the previous studies of miR-124 in MDS have focused on epigenetic changes and little is known about the underlying mechanism through which miR-124 regulates CDK6 expression.ResultsIn the present study, we employed pyrosequencing analysis to quantify the methylation levels of upstream regions of the miR-124 genes (miR-124-1, miR-124-2 and miR-124-3) in 56 primary MDS patients. We found the three miR-124 genes were methylated in MDS patients. Univariate analysis revealed that the World Health Organization (WHO) classification, marrow blast count, karyotype, International Prognostic Scoring System (IPSS), mean corpuscular volume, as well as high methylation of miR-124-1, miR-124-2 and miR-124-3 were significantly related to overall survival. In leukaemia-free survival, patients who were older and had an advanced WHO classification, high marrow blast counts, high IPSS risk and high methylation of miR-124-1 and miR-124-2 progressed rapidly to acute myeloid leukaemia. Multivariate analysis demonstrated that high methylation of miR-124-3 was an independent factor of overall survival. Median survival of patients with high miR-124-3 methylation was significantly shorter (7.6 months) than patients with low methylation (32.7 months; P = 0.010). A functional study revealed that silencing of miR-124 resulted in upregulation of its target gene, cyclin dependent kinase CDK6, which in turn promoted cell proliferation in the MDS cell line SKM-1.ConclusionsHigh methylation of miR-124-3 predicts shorter survival for patients with MDS, which may be a useful prognostic marker in MDS.
Highlights
Aberrant CpG island methylation has been increasingly recognized as a common event in myelodysplastic syndrome (MDS)
In this study, we found that miR-124 genes were highly methylated in MDS patients, and increased methylation levels of several CpG sites are associated with shorter overall survival (OS) or leukaemia-free survival (LFS)
(See figure on previous page.) Fig. 3 miR-124 suppresses cells proliferation and downregulates the expression of CDK6 in SKM-1 cell line. a Methylation status of miR-124 inSKM-1 cells before and after 4 μM DAC treatment for 48 h. b SKM-1 cells were treated with 2 and 4 μM DAC for 48 h, and miR-124 expression was determined by real-time PCR and normalized to U6
Summary
Aberrant CpG island methylation has been increasingly recognized as a common event in myelodysplastic syndrome (MDS). MicroRNAs (miRNAs) are a group of small noncoding RNAs consisting of 18–22 nucleotides that negatively regulate mRNA transcripts, typically by base pairing with a complementary region in the 3′untranslated region (3′-UTR) of the target gene [5]. They play pivotal roles in a wide range of biological processes including proliferation, apoptosis and differentiation [6]. Most of the previous studies of miR-124 in MDS have focused on epigenetic changes and little is known about the underlying mechanism through which miR-124 regulates CDK6 expression
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