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In this study, we define the individual and combined contribution of KAT6A, KAT6B, and KAT7 in a range of AML models, showing that although KAT6A\/B inhibition is efficacious in some preclinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with menin and the mixed lineage leukemia (MLL) complex and is colocalized at chromatin to coregulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6\/KAT7 provides an orthogonal route to targeting menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription, and overcomes primary resistance to menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic\/nongenetic resistance to menin inhibition, providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study provides the molecular rationale for combined targeting of KAT6\/7 and menin in MLL leukemia. It reveals that combination therapy results in a rapid and profound repression of the MLL transcriptional program leading to marked differentiation and loss of leukemia-initiating capacity, setting the platform for clinical translation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1517","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T10:02:07Z","timestamp":1750327327000},"page":"2117-2138","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Catalytic Inhibition of KAT6\/KAT7 Enhances the Efficacy and Overcomes Primary and Acquired Resistance to Menin Inhibitors in MLL Leukemia"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1675-3766","authenticated-orcid":false,"given":"Shellaina J.V.","family":"Gordon","sequence":"first","affiliation":[{"name":"1Peter MacCallum Cancer Centre, Melbourne, 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