Single missense mutations within the Runt domain severely diminish or even ablate binding Runx1 DNA binding and are associated with myelodysplasia and the development of acute myeloid leukemia, perhaps by haploinsufficiency and lowered gene dosage or by interference with the homodimerization of wildtype Runx1 or its binding to CBFβ. Here, RUNX1 is linked to acute myeloid leukemia.