Fig. 7

Schematic model for DOT1L and other epigenetic regulator-mediated gene transcription mechanisms and pharmacological inhibition. a Schematic model of the possible DOT1L and menin inhibition-mediated downregulation of MLL fusion target gene expression in MLL-rearranged leukemias. The intact MLL complex stably binds to its target genes via menin and recruits the DOT1L complex to drive target gene expression. Dual inhibition may disrupt the integrity of the oncogenic MLL complex and target gene activation. b Working model of possible DOT1L inhibition and SIRT1 activation. SUV39H1 and SIRT1 increase H3K9 methylation and decrease H3K9 acetylation, and DOT1L inhibits the chromatic localization of SIRT1 and SUV39H1, thereby maintaining an open chromatin state with elevated H3K9 acetylation, elevated H3K79 methylation, and minimal H3K9 methylation at MLL fusion protein target gene promoters. c Schematic model of the dual inhibition of DOT1L and BRD4. BRD4 binds K3K27ac and associates with SEC to allow phosphorylation and activation of RNA Pol II. DOT1L methylates H3K79 via H4 acetylation mediated by EP300, which regulates BRD4 binding to chromatin and the subsequent transcriptional gene expression in MLL leukemogenesis. d Schematic model for the dual inhibition of DOT1L and LSD1. LSD1 demethylates mono- and dimethylated lysine residues 4 and 9 on histone H3 (H3K4me1/2 and H3K9me1/2, respectively). LSD1 has been implicated as a drug target for leukemia, and dual inhibition of DOT1L and LSD1 has a synergistic effect. e Schematic model of dual inhibition of DOT1L and SEC or CDK9. As the largest pTEFb complex, the SEC complex is composed of CDK9, cyclin T, ELL1/ELL2, AFF1/AFF4, and ENL/AF9. Several translocation partners of MLL associate with ELL and pTEFb in SEC and lead to the misregulation of transcriptional elongation, such as HOX genes. Dual inhibition would improve efficacy by targeting these two parts of a developing and complex chromatin signaling pathway, including transcriptional elongation and histone methylation