Upon forced expression of NR4A1 in human AML cells, we found that binding of NR4A1 at the MYC SE is sufficient to decommission the activation status of the SE by suppressing the recruitment of essential coactivators including BRD4, Mediator and p300, leading to loss of p300-dependent H3K27 acetylation and Pol 2-dependent eRNA transcription. Here, NR4A1 is linked to acute myeloid leukemia.