Menin functions as an obligate chromatin scaffold, anchoring KMT2A (MLL) fusion complexes to HOX loci in concert with LEDGF and the SEC/DOT1L machinery, sustaining a HOX/MEIS-high transcriptional state that defines KMT2A-rearranged leukemia and ∼30% of NPM1-mutated AML (Niscola et al., 2025). Here, DOT1L is linked to acute myeloid leukemia.