Epigenetic Alterations caused by Decreased Cellular Methylation Potential Induce Fas‐FasL‐mediated Apoptotic Death in Leukemic T Lymphocytes

The transmethylation (TM) pathway is up regulated in proliferating T cells and transformed T leukemic cells but not in resting T cells, making it an ideal target to eliminate leukemic T cells. The TM pathway involves methyltransferase‐mediated conversion of S‐adenosylmethionine (SAM) to S‐adenosylhomocysteine (SAH). SAH is a potent feedback inhibitor of methyltransferases and is hydrolyzed by S‐adenosylhomocysteine hydrolase (SAHH), which determines the SAM: SAH ratio, known as the cellular methylation potential. The role of cellular methylation potential in the regulation of cell death in T leukemic cell lines was examined by inhibiting SAHH using pharmacologic SAHH inhibitors and RNAi. We demonstrate that a decrease in cellular methylation potential induces apoptosis in leukemic T lymphocytes. SAHH inhibitor treatment increases expression of FasL protein and activates the Fas‐FasL signaling pathway. Additionally, we observed an up regulation of FasL mRNA expression in leukemic T cells. ChIP analysis of histone H3 modifications at the FasL promoter showed increased transcriptional activation marks, namely acetylation at lysine 9 and 14, trimethylation at lysine 4 and increased recruitment of RNA Polymerase II. Overall, the data indicate the mechanistic role of cellular methylation potential in transcriptional regulation of FasL gene resulting in enhanced leukemic T cell death.