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Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal protein (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. In this study, we investigated immediate epigenetic and transcriptional responses following BET inhibition and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback that attenuates down-regulation, or even increases expression, of specific transcriptional modules. This adaptation is marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity to improve outcomes by combining BET- and p300- inhibition. p300 activity is required during all steps of resistance adaptation, however, the specific transcriptional programs that p300 regulates to induce resistance to BET inhibition differ in part between AML subtypes. As a consequence, in some AMLs the requirement for p300 is highest during earlier stages of resistance to BET inhibition, where p300 regulates transitional transcriptional patterns that allow leukemia-homeostatic adjustments. In other AMLs, p300 shapes a linear resistance to BET inhibition and remains crucial throughout all stages of the evolution of resistance. Altogether, our study elucidates the mechanisms that underlie an "acute" state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to mediate "chronic" resistance. Importantly, our data also suggest that sequential treatment with BET- and p300-inhibition may prevent resistance development, thereby improving outcomes., (Copyright © 2024 American Society of Hematology.)