A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia [ChIP-seq]

Treatment of cells carrying MLL-rearrangements with VTP-50469 (specific Menin-MLL1 inhibitor) displaces Menin from high molecular weight complexes and chromatin genome-wide. Since VTP-50469 block Menin interaction with MLL1 we tested using chip-seq if treatment with VTP-50469 also displaces MLL1 or MLL-fusions from chromatin. We found that the VTP-50469 treatment displaced MLL-fusions from only a subset of MLL-fusion binding sites. Since DOT1L is associated with MLL-AF9 we then tested if displacement of MLL1 also leads to loss of DOT1L association with chromatin on MLL-AF9 binding sites. We found that DOT1L binds to thousands of genes, treatment with VTP-50469 leads to genome wide loss of DOT1L binding including the same subset of MLL-fusion binding sites. Overall design: Using ChIP-seq we examined Menin, MLL1, and DOT1L genome binding sites as well as methylation of lysine 79 on Histone H3 (H3K79me2) in cell lines carrying MLL-rearrangements MOLM13 (MLL-AF9), RS4;11 (MLL-AF4) and ML-2 (MLL-AF6) treated with VTP-50469 (100-330nM) or DMSO for 2-4 days.