Expression Profiles of DNA Methylation and Demethylation Machinery Components in Pediatric Myelodysplastic Syndrome: Clinical Implications.

PURPOSE

The aim of this study was to analyse the expression profiles of (components of DNA methylation machinery), and (components of DNA demethylation machinery) in pediatric MDS patients and investigate their associations with MDS subtypes, cytogenetics, evolution to acute myeloid leukemia (AML) and methylation level.

PATIENTS AND METHODS

The expressions of , and were evaluated in 39 pediatric MDS patients by real-time quantitative PCR (qPCR). The quantification of methylation levels (MtL) was performed in 20 pediatric MDS patients by pyrosequencing. Mann-Whitney test was used to evaluate possible differences between the expression levels of selected in patients and donors, according to MDS subtypes, karyotypes, evolution to AML and MtL. The correlations between the expression levels of the different genes were assessed by Spearman rank correlation coefficient.

RESULTS

We found that s expression levels were higher in pediatric MDS compared to donors [ (p<0.03), (p<0.03), (p<0.02)]. and expression levels did not show a statistically significant difference between pediatric patients and donors. Considering MDS subtypes, patients at initial stage presented overexpression (p<0.01), while (p<0.02) and (p<0.007) were overexpressed in advanced subtypes. and expression did not differ in MDS subtypes. (p<0.03), (p<0.03), and (p<0.04) expression was higher in patients with normal karyotypes, while patients with abnormal karyotypes showed higher expression (p<0.03). Karyotypes had no association with expression. overexpression was observed in patients who showed disease evolution. A positive correlation was found between s expression and between and /. However, expression was not correlated with s or MtL was higher in pediatric MDS patients compared with donors (<0.03) and its hypermethylation was associated with increased expression (<0.009).

CONCLUSION

Our results suggest that the overexpression of and an imbalance between the expressions of the DNA methylation/demethylation machinery components play an important role in MDS development and evolution to AML. These results have clinical implications indicating the importance of inhibitors for preventing or delaying the progression to leukemia in pediatric MDS patients.