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LSD1 (KDM1A) inhibitors reduce symptoms and clonal burden in MPN, but whether these compounds may be effective in advanced disease stages remained so far elusive. Using a chromatin-focused CRISPR-Cas9 screen, we identified the histone methyltransferase DOT1L as a synthetic lethal target under pharmacologic LSD1 inhibition. DOT1L knockout impaired cellular fitness, reduced proliferation, and prolonged survival in xenografts. Furthermore, genetic inactivation of DOT1L increased LSD1 inhibitor sensitivity up to 100-fold resulting in cell cycle arrest and apoptosis induction in TP53 mutant blast-phase MPN. Mechanistically, we have identified a novel, non-canonical function of DOT1L which co-occupied LSD1-bound enhancers and contributed to the repression of transcriptional programs independent of its enzymatic activity. DOT1L loss cooperated with LSD1 inhibitors to activate tumor suppressive programs, while pharmacologic inhibition of DOT1Ls catalytic activity failed to elicit comparable effects. These findings indicate that leveraging DOT1L targeting via protein degradation or RNA interference, rather than conventional enzymatic inhibition, could enhance the therapeutic efficacy of LSD1 inhibitors in blast-phase MPN.<\/jats:p>","DOI":"10.1038\/s41375-025-02719-y","type":"journal-article","created":{"date-parts":[[2025,8,8]],"date-time":"2025-08-08T06:38:17Z","timestamp":1754635097000},"page":"2406-2418","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The histone-methyltransferase DOT1L cooperates with LSD1 to control cell division in blast-phase MPN"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2178-0680","authenticated-orcid":false,"given":"Karl","family":"Kapahnke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Plenge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1629-5664","authenticated-orcid":false,"given":"Tabea","family":"Klaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1558-9471","authenticated-orcid":false,"given":"Manoj K.","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Disha","family":"Anand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2372-9158","authenticated-orcid":false,"given":"Tamer T.","family":"\u00d6nder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Perner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tina M.","family":"Schn\u00f6der","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-6152","authenticated-orcid":false,"given":"Felicitas R.","family":"Thol","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5553-1173","authenticated-orcid":false,"given":"Frederik","family":"Damm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2438-1955","authenticated-orcid":false,"given":"Florian H.","family":"Heidel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-3321","authenticated-orcid":false,"given":"Florian","family":"Perner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,8,8]]},"reference":[{"key":"2719_CR1","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1182\/blood.2022017578","volume":"141","author":"D Luque Paz","year":"2023","unstructured":"Luque Paz D, Kralovics R, Skoda RC. 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FP received travel support from Syndax Pharmaceuticals and CHARM Therapeutics. FD reports personal fees from AbbVie, Amgen, AstraZeneca, BeiGene, Gilead, Incyte, Johnson&Johnson, Novartis, Roche, and SOBI. All other authors have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All experimental methods and procedures were performed in accordance with the relevant guidelines and regulations. The work with primary human specimens was approved by the institutional review board of Hannover Medical School (ethical votes 936\/2011 and 3432-2016) and written informed consent was obtained according to the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}