demonstrate that the Forkhead factor FOXC1 recruits a repressor complex of RUNX1, HDAC1, and Groucho family member TLE3 to a discrete set of enhancers distributed close to genes controlling monocyte/macrophage differentiation, thereby contributing to the differentiation block, which is the pathognomonic feature of acute myeloid leukemia. Here, FOXC1 is linked to acute myeloid leukemia.