Targets of epigenetic therapies. Examples of epigenetic drugs developed to treat aberrant DNA methylation and chromatin in myeloid malignancies. Nucleoside analogs like AZA are incorporated into the DNA and inhibit DNMT activity, resulting in DNA hypomethylation. Mutant IDH1 and IDH2 (IDH1/2-mut) convert α-KG normally produced by wild-type enzymes into oncometabolite 2-HG, and the oncogenic effects caused by 2-HG can be reversed by IDH1 and IDH2 inhibitors ivosidenib and enasidenib, respectively. Chromatin complexes that drive leukemic gene expression or inhibit differentiation programs can also be targeted. Disruption of MLL fusion complexes includes inhibition of DOT1L methyltransferase by pinometostat and menin by menin inhibitors (MIs). Bromodomain and extra terminal (BET) inhibitors (BETi) target the bromodomains of BET proteins like bromodomain-containing protein 4 (BRD4) to prevent their binding to acetylated histones and interaction with transcription factors that promote leukemic gene expression programs. Conversely, repressed differentiation programs can be reversed with the use of LSD1 inhibitors (LSD1i). Disrupting the interaction between LSD1, GFI, and the CoREST repressive complex allows for upregulation of critical myeloid transcription factors and differentiation. me1, monomethylation; me2, dimethylation; NADP, NAD phosphate; NADPH, reduced NAD phosphate. Professional illustration by Somersault18:24.