Objectives: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
© 2012 John Wiley & Sons A/S.