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

Cells carrying MLL-rearrangements are sensitive to treatment with VTP-50469 with IC50 in 20-60 nM. We treated MOLM13 or RS4;11 cells with DMSO (0.33%) or VTP-50469 (100-330nM), followed by digital gene expression analyses of 3'end RNA-seq data. We found that very few genes significantly change expression >2-fold after 2 days of treatment, while after 7-day treatment more genes significantly changed expression >2-fold. The genes that lost expression after VTP-50469 treatment were enriched in MLL-fusion target genes and DOT1L-sensitive genes. Moreover, treatment with both EPZ-5676 and VTP-50469 suppress similar subsets of genes, however VTP-50469 suppress genes faster as compared to EPZ-5676. Treatment of PDX with VTP-50469 suppressed similar gene sets, namely MLL-fusion targets and DOT1L-sensitive genes. Using 3-end RNA-seq followed by digital gene expression analyses we assessed genes that change expression upon treatment with VTP-50469 in cell lines (2 and 7 days) and PDX (28 day dosing) in triplicates of samples.