Crit Rev Oncol Hematol 2014 Apr 12;90(1):1-16. Epub 2013 Oct 12.
Ludwig Boltzmann Cluster Oncology, Vienna, Austria; Ludwig Boltzmann Institute for Leukemia Research and Hematology, Hanusch Hospital, Vienna, Austria; 3rd Medical Department, Hanusch Hospital, Vienna, Austria.
Disordered stem cell epigenetics and apoptosis-regulating mechanisms contribute essentially to the pathogenesis of myelodysplastic syndromes (MDS) and may trigger disease-progression to secondary acute myeloid leukemia (AML). Expression of apoptosis-mediators FAS (CD95) and DAPK1 the latter being also known for its association with autophagy are upregulated in neoplastic cells in patients with low-risk MDS and epigenetically silenced and downregulated in high-risk MDS and AML as confirmed by a study 50 MDS and 30 AMLs complementing this review. 5-Azacytidine (AZA) and 5-aza-2'deoxycytidine (DAC), promoted FAS and DAPK1 gene demethylation and their (re)expression as well as apoptosis in leukemic cell lines (HL-60, KG1) which can be reversed by siRNA against FAS. Thus, promoter-demethylation of FAS and DAPK1 represents a critical mechanism of drug-induced apoptosis in neoplastic cells in MDS and AML which underscores the clinical implication of epigenetically active therapies.