Epigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies

Liu, Hong Bin; Pattie, Phillip; Chandrasekara, Sahan; Spencer, Andrew; Dear, Anthony E.

doi:10.3892/ol.2016.4912

Cited by 13 publications

(8 citation statements)

References 24 publications

(22 reference statements)

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“…Castoro et al reported the methylation status of miR-124-1 and miR-124-3 in MDS patients and suggested that the re-expression of miR-124 was a good marker of response to DAC [ 21 ]. Another recent study also demonstrated that high-risk MDS or AML patients who responded to epigenetic treatment showed significant induction of miR-124 and inhibition of CDK4 and CDK6 expression [ 39 ]. However, the role of miR-124 in cell proliferation and the regulation of its target have not been clearly elucidated in vitro.…”

Section: Discussionmentioning

confidence: 99%

Pyrosequencing quantified methylation level of miR-124 predicts shorter survival for patients with myelodysplastic syndrome

et al. 2017

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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0388-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Pyrosequencing quantified methylation level of miR-124 predicts shorter survival for patients with myelodysplastic syndrome

et al. 2017

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“…PBMCs from patients which responded to the combination EGT for high risk MDS or AML demonstrated in vitro significant induction of miR-124 and inhibition of CDK4 and CDK6 (and a trend to inhibit EZH2) mRNA expression. These findings suggest miRNA-124 is a potential biomarker of early response to EGT in myeloid malignancies and a possible therapeutic target ( 45 ).…”

Section: Mirnas Associated With Good Prognosis Of Aml and Their Potenmentioning

confidence: 97%

“…miR-124 expression is inhibited in myelodysplastic syndrome (MDS) and is upregulated in response to epigenetic treatment (EGT) ( 45 , 102 ). The upregulation of miR-124 expression in response to single-agent EGT with either azacytidine (AZA) or the histone deacetylase inhibitor panobinostat (LBH589) reported in vitro in the HL60 leukemic cell line ( 45 ) resulted in inhibition of CDK4, CDK6 and EZH2 expression. Accordingly, combination with EGT led to a significant and additive inhibitory effect.…”

Section: Mirnas Associated With Good Prognosis Of Aml and Their Potenmentioning

confidence: 99%

MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization

et al. 2021

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Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue.

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“…Histone modification may activate or inhibit miRNA expression. HDAC inhibition upregulates miR-124 accompanied by the inhibition of the expression of downstream targets, such as CDK4, CDK6, and EZH2 ( 56 ). miRNA may also regulate histone modifications.…”

Section: Histone Methylation Modificationmentioning

confidence: 99%

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

Yang

Luan

Yuan

et al. 2021

Front. Cardiovasc. Med.

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The epidemic of cardiovascular diseases (CVDs) is predicted to spread rapidly in advanced countries accompanied by the high prevalence of risk factors. In terms of pathogenesis, the pathophysiology of CVDs is featured by multiple disorders, including vascular inflammation accompanied by simultaneously perturbed pathways, such as cell death and acute/chronic inflammatory reactions. Epigenetic alteration is involved in the regulation of genome stabilization and cellular homeostasis. The association between CVD progression and histone modifications is widely known. Among the histone modifications, histone methylation is a reversible process involved in the development and homeostasis of the cardiovascular system. Abnormal methylation can promote CVD progression. This review discusses histone methylation and the enzymes involved in the cardiovascular system and determine the effects of histone methyltransferases and demethylases on the pathogenesis of CVDs. We will further demonstrate key proteins mediated by histone methylation in blood vessels and review histone methylation-mediated cardiomyocytes and cellular functions and pathways in CVDs. Finally, we will summarize the role of inhibitors of histone methylation and demethylation in CVDs and analyze their therapeutic potential, based on previous studies.

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Epigenetic regulation of miRNA-124 and multiple downstream targets is associated with treatment response in myeloid malignancies

Cited by 13 publications

References 24 publications

Pyrosequencing quantified methylation level of miR-124 predicts shorter survival for patients with myelodysplastic syndrome

Pyrosequencing quantified methylation level of miR-124 predicts shorter survival for patients with myelodysplastic syndrome

MicroRNAs Associated With a Good Prognosis of Acute Myeloid Leukemia and Their Effect on Macrophage Polarization

Histone Methylation Related Therapeutic Challenge in Cardiovascular Diseases

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