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Developmental transcription programs are epigenetically regulated by multi‐protein complexes, including the menin‐ and MLL‐containing trithorax (TrxG) complexes, which promote gene transcription by depositing the H3K4me3 activating mark at target gene promoters. We recently reported that in Ewing sarcoma, MLL1 (lysine methyltransferase 2A, KMT2A) and menin are overexpressed and function as oncogenes. Small molecule inhibition of the menin–MLL interaction leads to loss of menin and MLL1 protein expression, and to inhibition of growth and tumorigenicity. Here, we have investigated the mechanistic basis of menin–MLL‐mediated oncogenic activity in Ewing sarcoma. Bromouridine sequencing (Bru‐seq) was performed to identify changes in nascent gene transcription in Ewing sarcoma cells, following exposure to the menin–MLL interaction inhibitor MI‐503. Menin–MLL inhibition resulted in early …