GSE127298
A novel Menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia
Inhibition of the Menin (encoded by MEN1) and MLL1 (KMT2A) protein-protein interaction has been proposed as a potential targeted therapeutic strategy for MLL-rearranged (MLL-r) leukemia. We sought to develop more potent and selective Menin-MLL1 interaction inhibitors that are effective in vitro and in vivo to directly assess potential therapeutic opportunities. Structure-based design yielded the potent, highly selective and orally-bioavailable small molecule inhibitor VTP-50469. Human cell lines carrying MLL-rearrangements were highly sensitive and selectively responsive to treatment with VTP-50469. VTP-50469 displaced Menin from high molecular weight protein complexes and inhibited chromatin occupancy of MLL1 at select target genes. Loss of MLL1 binding led to specific changes in gene expression, cellular differentiation, and apoptosis. Mice engrafted with leukemia cells isolated from patients with either MLL-r AML or MLL-r ALL showed dramatic reductions of leukemia burden and prolonged survival when treated with VTP-50469. Remarkably, multiple mice engrafted with MLL-r ALL remained disease free greater than 1 year following cessation of treatment. Therefore, inhibition of the Menin-MLL1 interaction with VTP-50469 is highly effective in patient-derived xenograft (PDX) models of human MLL-r AML and MLL-r ALL which supports rapid translation of this approach to clinical trials. This submission represents the scRNAseq component of the study. Overall design: Single cell sequencing of full-length transcripts (scRNA-seq) was used to investigate molecular profiles of ALL PDX cells in response to VTP-50469 treatments for 28 days.