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Proteolysis-targeting chimeras (PROTACs) that induce proteasomal degradation of mutated FLT3 emerge as innovative pharmacological approach. Molecular mechanisms that control targeted proteolysis beyond the ubiquitin-proteasome-system are undefined and PROTACs are the only known type of FLT3 degraders. We report that the von-Hippel-Lindau ubiquitin-ligase based FLT3 PROTAC MA49 (melotinib-49) and the FLT3 hydrophobic tagging molecule MA50 (halotinib-50) reduce endoplasmic reticulum-associated, oncogenic FLT3-ITD but spare FLT3. Nanomolar doses of MA49 and MA50 induce apoptosis of human leukemic cell lines and primary AML blasts with FLT3-ITD (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05-0.0001), but not of primary hematopoietic stem cells and differentiated immune cells, FLT3 wild-type cells, retinal cells, and c-KIT-dependent cells. In vivo activity of MA49 against FLT3-ITD-positive leukemia cells is verified in a <jats:italic>Danio rerio<\/jats:italic> model. The degrader-induced loss of FLT3-ITD involves the pro-apoptotic BH3-only protein BIM and a previously unidentified degrader-induced depletion of protein-folding chaperones. The expression levels of HSP90 and HSP110 correlate with reduced AML patient survival (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.1) and HSP90, HSP110, and BIM are linked to the expression of FLT3 in primary AML cells (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). HSP90 suppresses degrader-induced FLT3-ITD elimination and thereby establishes a mechanistically defined feed-back circuit.<\/jats:p>","DOI":"10.1038\/s41375-024-02405-5","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T08:03:14Z","timestamp":1726732994000},"page":"2561-2572","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Selective degradation of mutant FMS-like tyrosine kinase-3 requires BIM-dependent depletion of heat shock proteins"],"prefix":"10.1038","volume":"38","author":[{"given":"Melisa","family":"Halilovic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Abdelsalam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Zabkiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Lazenby","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4391-9802","authenticated-orcid":false,"given":"Caroline","family":"Alvares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1511-6212","authenticated-orcid":false,"given":"Walburgis","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Najafi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ina","family":"Oehme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Hieber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-8149","authenticated-orcid":false,"given":"Yanira","family":"Zeyn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Bros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-9261","authenticated-orcid":false,"given":"Wolfgang","family":"Sippl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3973-045X","authenticated-orcid":false,"given":"Oliver H.","family":"Kr\u00e4mer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,9,17]]},"reference":[{"key":"2405_CR1","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.3390\/cancers12102806","volume":"12","author":"JP M\u00fcller","year":"2020","unstructured":"M\u00fcller JP, Schmidt-Arras D. 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Cell Chem Biol. 2022;29:398\u2013411.","journal-title":"Cell Chem Biol"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02405-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02405-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02405-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T11:02:52Z","timestamp":1732532572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-024-02405-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,17]]},"references-count":54,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2024,12]]}},"alternative-id":["2405"],"URL":"https:\/\/doi.org\/10.1038\/s41375-024-02405-5","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,17]]},"assertion":[{"value":"3 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 September 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"OHK declares the patents WO2019\/034538, WO2016020369A1, and WO\/2004\/027418, and paid advisory work for the BASF Ludwigshafen, Germany. WO2019\/034538 (Synthesis, Pharmacology and use of New and Selective FMS-like tyrosine kinase 3 (FLT3) FLT3 Inhibitors) covers substance classes that are discussed in this work. The substances that are covered in these patents are not the same that are shown in the submitted manuscript. The BASF has not influenced our study, and its products are not discussed in the manuscript. Thus, there are no direct competing interests. All other authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Peripheral blood and bone marrow samples were obtained from AML patients with written informed consent in accordance with the Declaration of Helsinki under ethical approval REC: 17\/LO\/1566. Institutional Review Board Statement Zebrafish husbandry (permit number 35-9185.64\/BH Hassel) and experiments (permit number 35-9185.81\/G-126\/15) were performed according to local animal welfare standards (Tierschutzgesetz \u00a711, Abs. 1, No. 1) and in accordance with European Union animal welfare guidelines (EU Directive 2010\/63\/EU). All applicable national and institutional guidelines for the care and use of zebrafish were followed. C57BL\/6 mice were bred and maintained in the Central Animal Facility of the Johannes Gutenberg-University Mainz under specific pathogen-free conditions on a standard diet according to the guidelines of the regional animal care committee. The \u201cPrinciples of Laboratory Animal Care\u201d (NIH publication no. 85-23, revised 1985) were followed. Mice at 12 weeks of age were sacrificed for organ retrieval according to \u00a7 4(3) TierSchG.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}