Glutathione S-transferase P (GSTP) 1 and prostaglandin-endoperoxide synthase (PTGS) 2 genes are commonly silenced by promoter hypermethylation in various cancers. However, these epimutations remain poorly investigated in leukemia and lymphoma. We hypothesized that DNA methylation-induced GSTP1 and PTGS2 silencing may be involved in hematological malignancies. Our results demonstrated that methylation- associated silencing of GSTP1 and PTGS2 was found in various leukemia and lymphoma cell lines. A correlation was found between GSTP1 chromatin structure and GSTP1 transcriptional state. Interestingly, PTGS2 hypermethylation was observed in many samples from patient with hematological malignancies presenting reduced PTGS2 expression levels. By extending our study to other epigenetically regulated genes, we observed differential proliferation, cell death and DNA demethylation responses of blood cancer cell lines to the DNA demethylating agent 5-aza-2″-deoxycytidine. In conclusion, we identified DNA methylation signatures that could be promising clinical biomarkers in hematological malignancies. Finally, our study provides critical data for a better understanding of the mechanism of action and effects of 5-aza-2″-deoxycytidine that could provide guidance to predict sensitivity and response for a therapeutic use of this compound against hematological malignancies and potentially other cancers.