These findings indicate that the overexpression of KDM6B associated with ASXL1 mutation in human leukemia cells renders them highly vulnerable to targeted inhibition of KDM6B, and provide solid preclinical evidence for the potential of pharmacologic inhibition of KDM6B for the treatment of ASXL1 mutation–associated myeloid malignancies. Here, ASXL1 is linked to myeloid neoplasm.