The clinical impact of DNA methylation frequencies of JAK2 negative regulators in patients with essential Thrombocythemia

Födermayr, Mathilde; Zach, Otto; Huber, Maria; Machherndl‐Spandl, Sigrid; Wölfl, S; Bösmüller, H.; Hasenschwandtner, Sonja; Burgstaller, Sonja; Krieger, O.; Lutz, D.; Weltermann, Ansgar; Hauser, Hanns

doi:10.1016/j.leukres.2012.01.008

Cited by 2 publications

(3 citation statements)

References 17 publications

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“…Using MSP primers in the 5′UTR, SOCS3 methylation was not detected in any of the patients with PV or ET [22]. However, Fourouclas et al demon- Fourouclas [22] Capello [20] Quentmeier* [30] Fernandez -Mercado [21] Teofili [29] Barrio † [19] Fodermayr [34] No of case strated SOCS3 methylation in 27% patients with PMF, suggesting a disease-specific SOCS3 methylation among MPN [22]. Unfortunately, in our series, we had too few patients with PMF to verify this finding.…”

Section: Discussioncontrasting

confidence: 59%

“…had methylation of SOCS1 [21, 22] (Figure S1). In contrast, studies using MSP primers inside the 3′translated exonic sequence showed methylation frequencies ranging from 12.8% to 72% (median: 14.5%) [20–23, 29, 34] (Figure S1). Therefore, these findings were consistent with the notion that a boundary exists between methylated and unmethylated CpG dinucleotide within a CpG island, and that CpG dinucleotide inside the 3′translated protein-coding sequences is commonly methylated in normal cells.…”

Section: Discussionmentioning

confidence: 98%

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Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia‐negative myeloproliferative neoplasm

Zhang

Fung

Chen

et al. 2013

J Cellular Molecular Medi

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Janus kinase-signal transducer and activator of transcription (JAK/STAT) signalling, pivotal in Philadelphia-negative (Ph-ve) myeloproliferative neoplasm (MPN), is negatively regulated by molecules including SOCSs, CISH and SHP1. SOCS1, SOCS2 and SOCS3 methylation have been studied in MPN with discordant results. Herein, we studied the methylation status of SOCS1, SOCS2 and SOCS3, CISH and SHP1 by methylation-specific polymerase chain reaction (MSP) in cell lines and 45 diagnostic marrow samples of Ph-ve MPN. Moreover, we attempted to explain the discordance of methylation frequency by mapping the studied MSP primers to the respective genes. Methylation was detected in normal controls using SOCS2 MSP primers in the 3′translated exonic sequence, but not primers around the transcription start site in the 5′ untranslated regions (5′UTR). SOCS1, SOCS2, SOCS3 and CISH were completely unmethylated in primary MPN samples and cell lines. In contrast, methylation of SHP1 was detected in 8.9% primary marrow samples. Moreover, SHP1 was completely methylated in K562 cell line, leading to reversible SHP1 silencing. A review of methylation studies of SOCS1 and SOCS3 showed that spuriously high rates of SOCS methylation had been reported using MSP primers targeting CpG sites in the 3′translated exonic sequence, which is also methylated in normal controls. However, using MSP primers localized to the 5′UTR, methylation of SOCS1, SOCS2 and SOCS3 is infrequent across all studies. In summary, methylation of SOCS1, SOCS2, SOCS3 and CISH is infrequent in Ph-ve MPN. Appropriate MSP primers are important for accurate estimation of the methylation frequency. The role of SHP1 methylation in the pathogenesis of MPN warrants further investigation.

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Section: Discussioncontrasting

confidence: 59%

Section: Discussionmentioning

confidence: 98%

Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia‐negative myeloproliferative neoplasm

Zhang

Fung

Chen

et al. 2013

J Cellular Molecular Medi

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“…A recent clinical study on 39 patients with essential thrombocythemia, methylation-specific PCR analysis revealed no significant difference on increase in the methylation of SOCS3 or SOCS1 or PTPN6 compared with healthy individuals. Therefore methylation analysis of these negative regulators of Jak2 as a prognostic marker did not add to measurable values for ET patients characterized with myeloproliferative neoplasms [49]. Hypermethylation in the SOCS3 promoter region was also identified in sixteen out of sixty patients with Myelofibrosis but not in patients with PV or ET [50].…”

Section: Introductionmentioning

confidence: 99%

Methylation and microRNA-mediated epigenetic regulation of SOCS3

Boosani

Agrawal

2015

Mol Biol Rep

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Epigenetic gene silencing of several genes causes different pathological conditions in humans, and DNA methylation has been identified as one of the key mechanisms that underlie this evolutionarily conserved phenomenon associated with developmental and pathological gene regulation. Recent advances in the miRNA technology with high throughput analysis of gene regulation further increased our understanding on the role of miRNAs regulating multiple gene expression. There is increasing evidence supporting that the miRNAs not only regulate gene expression but they also are involved in the hypermethylation of promoter sequences, which cumulatively contributes to the epigenetic gene silencing. Here, we critically evaluated the recent progress on the transcriptional regulation of an important suppressor protein that inhibits cytokine-mediated signaling, SOCS3, whose expression is directly regulated both by promoter methylation and also by microRNAs, affecting its vital cell regulating functions. SOCS3 was identified as a potent inhibitor of Jak/STAT signaling pathway which is frequently upregulated in several pathologies, including cardiovascular disease, cancer, diabetes, viral infections, and the expression of SOCS3 was inhibited or greatly reduced due to hypermethylation of the CpG islands in its promoter region or suppression of its expression by different microRNAs. Additionally, we discuss key intracellular signaling pathways regulated by SOCS3 involving cellular events, including cell proliferation, cell growth, cell migration and apoptosis. Identification of the pathway intermediates as specific targets would not only aid in the development of novel therapeutic drugs, but, would also assist in developing new treatment strategies that could successfully be employed in combination therapy to target multiple signaling pathways.

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The clinical impact of DNA methylation frequencies of JAK2 negative regulators in patients with essential Thrombocythemia

Cited by 2 publications

References 17 publications

Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia‐negative myeloproliferative neoplasm

Methylation profiling of SOCS1, SOCS2, SOCS3, CISH and SHP1 in Philadelphia‐negative myeloproliferative neoplasm

Methylation and microRNA-mediated epigenetic regulation of SOCS3

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