Epigenetic regulators in acute myeloid leukemia.
A. The DNMT family converts cytosine residues to 5-methylcytosine and are responsible for somatic methylation patterns. DNMTmut creates aberrant methylation patterns and disruption of gene expression. Hypo-methylating agents, including azacitidine and decitabine, restore methylation through inhibition of DNMTmut, allowing for increased tumor suppressor gene expression.
B. TET2 modifies 5-methylcytosine to 5-hydroxymethylcytosine, resulting in DNA demethylation. TET2 is inhibited by 2-hydroxyglutarate (2HG), produced by mutated IDH1 or IDH2. IDH1 and IDH2 inhibitors indirectly restore methylation patterns and result in myeloid differentiation C. ASXL1 cooperates with BAP1 to deubiquitinate lysine 119 on histone H2, contributing to a gain-of-function effect and resulting in a differentiation block. Depletion of BAP1 restores HOX gene expression by decreasing HOX-mediated replicative immortality.