Findings presented here demonstrate for the first time that Menin depletion by CRISPR-Cas9 or Menin degradation by the dTAG system not only reduces MLL1/MLL-FP targets and induces differentiation and lethality, but also sensitizes AML cells with MLL1-r or mtNPM1 to BETi- or LSD1i-induced loss of viability. Here, MEN1 is linked to acute myeloid leukemia.