Exploring the role of the MLL1 complex in leukemia by small molecule targeting of an essential protein‐protein interaction

Abstract

MLL1 is a histone H3 lysine 4 (H3K4) specific methyltransferase that has essential functions in embryonic development, hematopoiesis and leukemia. Dysregulation of MLL1 activity, by mutation, translocation or amplification of one copy of the MLL1 gene, has been found to play an essential role in many cases of acute leukemia with poor prognosis. In most cases of MLL1‐associated leukemia, MLL1 wild‐type functions coordinately with the mutant copy of MLL1 to aberrantly overexpress MLL1 target genes, specifically HoxA9 and Meis1. Overexpression of these genes is essential for leukemogenesis. In the cell, MLL1 activity is upregulated by stable association of MLL1 with the proteins WDR5, RbBP5 and Ash2L. In this stable enzyme complex, WDR5 serves as the structural platform to mediate complex assembly and facilitate the interaction of RbBP5 and Ash2L with MLL1. We hypothesize that small molecule targeting of the MLL1:WDR5 interaction will downregulate MLL1 activity and provide a therapeutic avenue to treat MLL1‐involved leukemias. To this end, we have developed a potent, peptidomimetic inhibitor of the MLL1:WDR5 interaction. We have found that treatment of leukemia cell lines with this inhibitor downregulates expression of MLL1 target genes and has moderate inhibitory effects on cell viability in leukemia‐derived cell lines.