Mixed lineage leukemia protein 1 (MLL1) is one of the histone H3 lysine 4 (K4) methyltransferases in mammals and plays important roles in definitive hematopoiesis. Rearrangements of MLL1 gene including translocation, amplification and tandem duplication are common in acute leukemia, which have extremely poor prognosis. Based on biochemical characterization of the MLL1 complex, we have developed a potent and specific small-molecule inhibitor (MM-401) that targets MLL1 complex assembly and thus, its methyltransferase activity. We demonstrate that MM-401 selectively inhibits MLL1 dependent H3 K4 methylation in vitro and in cells. Using this newly developed probe, we show that although MLL mutations are drivers of leukemogenesis, wild type MLL1 is critical for viability of leukemia cells and can be a good therapeutic target. MM401 has high efficacy against MLL leukemia by inducing apoptosis, cell cycle arrest and myeloid differentiation of leukemic blasts while having little effects on normal bone marrow cells. Genome-wide transcriptome analyses show that MM-401 alters gene expression in the same manner as MLL1 deletion, underscoring the importance of MLL1 methyltransferase activity in disease progression as well as ‘on-target’ specificity of MM-401. We envision broad applications of MM-401 in basic and translational research.<br/><br/>

Targeting MLL1 complex assembly for inhibition of H3K4 methyltransferase activity

249th National Meeting (2015)

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