A molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition.

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacological, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic re-activation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin-inhibitors. These findings shed light on novel functions of evolutionary conserved epigenetic mediators like MLL1-Menin and MLL3/4-UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials.