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The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacological, and biochemical approaches in mouse and human systems, we discovered a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that MLL1-Menin safeguards leukemia survival by impeding binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of tumor suppressive genes, including factors associated with cell cycle arrest and cellular senescence. We show that this epigenetic mechanism is operative in murine and human models of AML, and clinical responses to Menin-MLL inhibition in primary human leukemia are also accompanied by induction of these tumor suppressive genes. We provide proof-of-concept in vivo evidence that this mechanism can be rationally exploited to design combination therapies using FDA-approved drugs (e.g. CDK4/6 inhibitors) to mitigate treatment resistance associated with MLL3/4-UTX complex mutations. These findings shed light on the context-dependent and often antagonistic roles that chromatin regulators exhibit in development and disease and provide mechanistic insight for rational design of targeted epigenetic therapies.

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