While several studies have documented the epigenetic effects of decitabine and azacitidine in vitro and invivo,[31-33] other studies have elucidated other mechanisms. As an example, it was recently shown that DAC upregulates p21 and induces cell cycle arrest in a DNA methyltransferase (DNMT)-independent fashion through DNA damage ATM/P53 axis, implicating the role of these pathways in responses.[34] However, the same group has demonstrated that neither DNA damage nor methylation changes were predictive of response to demethylating therapy.[35] Further, decitabine effects were studied by whole-genome expression assays in melanoma cells; p21 induction was observed and WNT pathway activation was found to be contributing to resistance. Interestingly, inhibition of the proteasome increased the growth arrest of DAC-treated cells, implying that proteasome inhibitors might act in synergy with epigenetic modifiers.[36] An interesting study looking at cytotoxic CDS+ T-cell responses to MAGE antigens has demonstrated that epigenetic therapy with a DNMT inhibitor induced such responses in vivo and was correlating with clinical responses in 8 out of 1 1 patients; thus, it is possible that unmasking MAGE antigens with epigenetic drugs caused immune clearance of leukemic cells.[3 7] Epigenetic drugs are known to induce differentiation, and a study recently described how both cytarabine and DAC were able to induce differentiation of embryonic cancer stem cells via caspase-mediated degradation of EZH2 as well as NANOG and OCT-4 stem cell factors, suggesting yet another mechanism of action of nucleoside analogues and epigenetic drugs operating at the stem cell level.[38]