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 integrat-ing chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, 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 safe-guards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional acti-vation of a tumor-suppressive program that dictates therapeutic responses in murine and human leuke-mia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These fi ndings shed light on novel functions of evolutionarily 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.SIGNIFICANCE: Menin-MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin-MLL inhibitor-resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses.

Automated summary

Menin interacts with oncogenic MLL1-fusion proteins, and disrupting these interactions can be a potential treatment for leukemia. The study found a molecular switch that determines the response to Menin-MLL inhibitors, involving MLL3/4-UTX chromatin-modifying complexes. By disrupting the Menin-MLL1 interaction, a tumor-suppressive program can be activated, and treatment resistance in leukemia cells can be overcome by using CDK4/6 inhibitors.