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We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts\u00a0and controlled ETO2 depletion models. We demonstrate that beyond its well\u2010established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2\u2010activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2\/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small\u2010molecule and PROTAC\u2010mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2\u2010activated transcripts. 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