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We evaluated DEK::NUP214 (DN), characterizing a distinct AML entity, for its dependency on XPO1 in human AML models. Deletion of XPO1 in DN-positive FKH-1 cells revealed a strong dependency on XPO1. Pharmacologic inhibition of XPO1 by the second-generation selective inhibitor of nuclear export, eltanexor, in primary human and FKH-1 cells reduced XPO1 expression, disrupted co-localization of XPO1 and DN, and induced apoptosis and cell cycle arrest. Functionally, XPO1 and DN co-localized at chromatin, and this co-localization was strongly reduced by XPO1 inhibition. Loss of chromatin binding resulted in downregulation of DN target genes and pathways related to cell cycle and self-renewal. Eltanexor treatment of a patient-derived DN-AML xenograft model disrupted leukemia development, showing molecular clearance in bone marrow after a median of 377 days in eltanexor-treated mice, while control mice succumbed after a median of 244 days. In summary, XPO1 stabilizes DN at chromatin to allow the activation of its oncogenic gene signature, while targeting XPO1 treats leukemia successfully in vivo. These findings establish XPO1 as a molecular target in DEK::NUP214 AML.<\/jats:p>","DOI":"10.1038\/s41375-025-02570-1","type":"journal-article","created":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T07:00:53Z","timestamp":1743058853000},"page":"1102-1113","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["XPO1-dependency of DEK::NUP214 leukemia"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-3941-7497","authenticated-orcid":false,"given":"Fiorella","family":"Charles Cano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold","family":"Kloos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rucha Y.","family":"Hebalkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Plenge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4409-016X","authenticated-orcid":false,"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Kirchhoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadine","family":"Kattre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"G\u00f6rlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guntram","family":"B\u00fcsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-0345","authenticated-orcid":false,"given":"Halyna R.","family":"Shcherbata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michaela","family":"Scherr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstanze","family":"D\u00f6hner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razif","family":"Gabdoulline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5318-9044","authenticated-orcid":false,"given":"Michael","family":"Heuser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,3,27]]},"reference":[{"key":"2570_CR1","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1182\/blood-2009-03-209262","volume":"114","author":"JW Vardiman","year":"2009","unstructured":"Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, et al. 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KD declares research funding from Novartis, Astellas, Agios, BMS\/Celgene, honoraria from Novartis, BMS\/Celgene, Daiichi Sankyo, Jazz, Roche, AOP, Abbvie and membership advisory committee: Abbvie. The other authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}