Aberrant promoter methylation of Dab2 gene in myelodysplastic syndrome

Human Disabled-2 (Dab2), a putative tumor suppressor gene, is frequently down-regulated in human tumors. This study aims to explore the association between Dab2 methylation status and expression in newly diagnosed myelodysplastic syndrome (MDS) patients and patients who received 5-aza-2'-deoxycytidine (decitabine) treatment, so as to determine the effect of Dab2 in the pathogenesis of MDS.

Methylation-specific polymerase chain reaction and bisulfite sequencing were used to detect the methylation status of Dab2 gene. Dab2 expression was investigated by using fluorescence quantitation RT-PCR (FQRT-PCR) and western blot analysis.

Hypermethylation of Dab2 gene was present in 50.6% of patients with MDS and was significantly correlated with the down-regulation of Dab2 mRNA and protein expression. There was a significant difference in methylation frequency between refractory anemia/refractory anemia with ringed sideroblasts/MDS associated with isolated del (5q) (RA/RARS/5q-) group (33.3%) and refractory anemia with excess blasts-1/-2 (RAEB-1/RAEB-2) group (73.3%). Significant difference was also observed between refractory cytopenia with multiline dysplasia group (37.8%) and RAEB-1/RAEB-2 group. In addition, higher frequency of hypermethylation was observed in intermediate-2-/high-risk group, compared to low-risk/intermediate-1-risk group (75.0% vs. 40.0%). Demethylating agent 5-aza-2'-deoxycytidine treatment could partly reverse hypermethylation and, hence, restore the expression of Dab2 gene.

The Dab2 gene is inactivated in MDS in part by DNA methylation, and the suppression of Dab2 expression by DNA methylation may play a role in the development of MDS.