ASXL1 mutant protein (ASXL1-MT) is associated with preleukemic states, including MDS. However, cooperating genetic and/or molecular changes are required for progression of ASXL1-MT–expressing preleukemic cells to AML. HHEX, a homeobox-containing DNA-binding protein, is overexpressed in AML and cooperates with ASXL1-MT to induce AML. HHEX mediates leukemia cell transformation by cooperating with ASXL1-MT to induce expression of MYB and ETV5, which are critical target genes for AML cell viability and prevention of differentiation.