The effect of epigenetic therapies on cell-intrinsic modulation of the immune system. Epigenetic therapies including hypomethylating agents and inhibitors of LSD1, EZH2, and HDACs have been shown to reactivate epigenetically silenced endogenous retroviruses (ERVs). Removal of repressive marks by these epigenetic drugs results in transcription of ERVs, leading to the formation of double-strand RNA (dsRNA) molecules in the nucleus. These are then detected by pattern recognition receptors (eg, melanoma differentiation–associated protein 5 [MDA5]) in the cytoplasm that typically sense dsRNAs originating from viruses. This dsRNA sensing leads to a state of “viral mimicry” via the initiation of a signaling cascade mediated by mitochondrial antiviral signaling protein (MAVS) and results in upregulation of the TFs IFN regulatory factor 3/7 (IRF3/7) and NFKB to induce an interferon (IFN) type I/III response. IFNI/III signals in an autocrine manner through the interferon α receptor (IFNAR) to culminate in transcription of the IFN response genes. This ultimately leads to upregulation of key immune molecules such as major histocompatibility complex (MHC) class 1 on the cell surface. Bromodomain and extra-terminal motif (BET) inhibition has been associated with decreased expression of the inhibitory molecule programmed death ligand 1 (PD-L1), increasing the visibility of the leukemic cell to the immune system. Conversely, hypomethylating agents can lead to increased expression of PD-L1, rendering the cell sensitive to checkpoint inhibition. BETi, BET inhibitor; EZH2i, EZH2 inhibitor; HDACi, HDAC inhibitor; LSD1i, LSD1 inhibitor.