To summarize, H3K27-modifying enzymes are central to AML pathogenesis: both loss of silencing and a failure to initiate activation (ASXL1/PRC2 dysfunction or UTX mutation, respectively) tips the balance toward pro-leukaemic gene expression programmes, both by directly de-repressing stemness genes and/or by indirectly reprogramming enhancer–promoter interactions. The gene discussed is ASXL1; the disease is acute myeloid leukemia.