Updated project metadata. Acute myeloid leukemia (AML) is a hematological malignancy characterized by the abnormal proliferation and accumulation of immature myeloid cells in the bone marrow. Inflammation plays a crucial role in AML progression, but excessive activation of inflammatory pathways can also trigger cell death. IRF2BP2 is a chromatin regulator that has been implicated in AML pathogenesis, although its precise role in this disease is not fully understood. In this study, we demonstrate that in AML cells IRF2BP2 interacts with the transcriptional heterodimer ATF7/JDP2, which is involved to activate inflammatory pathways in AML cells. We show that IRF2BP2 is recruited by the ATF7/JDP2 dimer to chromatin and counteracts its gene activating function. Loss of IRF2BP2 leads to the overactivation of inflammatory pathways, resulting in immediate cell death. Our findings suggest that a delicate balance of activating and repressive transcriptional mechanisms establishes a pro-oncogenic inflammatory set-up in AML cells, and that manipulation of the ATF7/JDP2-IRF2BP2 regulatory axis may offer a potential vulnerability for AML treatment. Thus, our study provides new insights into the molecular mechanisms underlying AML pathogenesis and identifies a potential therapeutic target for AML treatment.