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NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell\u2013associated genes in cooperation with epigenetic regulators. In this study, we show that MYST family histone acetyltransferase (HAT) complex proteins, including KAT6A\/MOZ, KAT7\/HBO1, and the common KAT6A\/7 complex subunit BRPF1, associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of KAT6A and KAT7 impairs NUP98-r cell fitness. KAT6A\/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A\/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with menin inhibitor treatment, and was efficacious in menin inhibitor\u2013resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r acute myeloid leukemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A\/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO\u2013driven leukemias.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-1772","type":"journal-article","created":{"date-parts":[[2025,6,19]],"date-time":"2025-06-19T10:02:02Z","timestamp":1750327322000},"page":"2096-2116","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in\n                    <i>NUP98<\/i>\n                    -Rearranged Acute Myeloid Leukemia"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9960-5119","authenticated-orcid":false,"given":"Nicole L.","family":"Michmerhuizen","sequence":"first","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, 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Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7935-9712","authenticated-orcid":false,"given":"Bright","family":"Arthur","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4846-4790","authenticated-orcid":false,"given":"Vibhor","family":"Mishra","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4329-3953","authenticated-orcid":false,"given":"Chun Shik","family":"Park","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5558-7967","authenticated-orcid":false,"given":"Danika","family":"Di Giacomo","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9267-9844","authenticated-orcid":false,"given":"Ryan","family":"Hiltenbrand","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, Tennessee."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9930-8499","authenticated-orcid":false,"given":"Qingsong","family":"Gao","sequence":"additional","affiliation":[{"name":"1Department of Pathology, St. Jude Children\u2019s Research Hospital, Memphis, 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