Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and is frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole genome CRISPR screens, we have identified specific roles for MTF2-PRC2.1, PCGF1-PRC1.1 and Menin- MLL1/2 complexes in maintaining bivalency. Unexpectedly, genetic loss or pharmacological inhibition of Menin phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. I will discuss the molecular mechanisms underpinning these observations and potential therapeutic opportunities that have been revealed for the repurposing of Menin-MLL inhibitors to overcome both oncogenic and immunosuppressive functions of polycomb.