In summary, our study reveals that the histone H3K36me2-specific methyltransferase ASH1L and its enzymatic activity play an important role in promoting the MLL-AF9-induced leukemogenesis, which provides an important molecular basis for targeting ASH1L and its enzymatic activity to treat MLL-AF9-induced leukemias. The gene discussed is KMT2A; the disease is leukemia.