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Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader.<\/jats:p>","DOI":"10.1038\/s41375-026-02883-9","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T07:18:08Z","timestamp":1771312688000},"page":"717-729","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A STAT3 degrader demonstrates efficacy in venetoclax resistant acute myeloid 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EHA Library. 2024;420127:P2040.","DOI":"10.1182\/blood-2024-210301"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02883-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02883-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02883-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:02:12Z","timestamp":1775559732000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-026-02883-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,17]]},"references-count":51,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["2883"],"URL":"https:\/\/doi.org\/10.1038\/s41375-026-02883-9","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,17]]},"assertion":[{"value":"11 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 February 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2026","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The following information was missing from the Acknowledgement section: AS received funding support for the work from the MDS Foundation Young Investigator Award 2021 and Kymera Therapeutics Sponsored Research Agreement.","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"SC received financial support from the Ceriale Postdoctoral Fellowship award. BRP was financially supported by the Einstein Aging Research Training Grant (T32): 5T32AG23475-22 and the Institutional Research and Academic Career Development Awards (IRACDA) Grant K12GM102779. DV was supported by K12CA279871 NCI career development award and Paul S. Frenette Scholar Award. KI is supported by NIH grants (R01DK098263, R01HL148852) and Blood Cancer United (8040-24). In the past 3 years AS has received reimbursement & honoraria for educational activities from PeerView, ACHL, Great Debates, HemeOnc Pulse, MJHS Lifesciences, VJ HemeOnc and Geron. Advisory board fees from Kymera Therapeutics, Geron, Ryvu Therapeutics, Caris Lifesciences. Research funding from Kymera Therapeutics and Ryvu Therapeutics and is on the Data Safety Monitoring Board for Servier Pharmaceuticals. A.V. has received research funding from BMS, Jannsen, MedPacto, Curis, Prelude, Halia and Ryvu, has received compensation as a scientific advisor to Stelexis Therapeutics, Calico and Aurigene and has equity ownership in Roshon, Stelexis and clinStreet. SBK had an SRA with Kymera Therapeutics. EG reports compensation for consulting and\/or equity ownership from BaxGen Therapeutics, BeanPod Biosciences, Comorin Therapeutics, Life Biosciences, Stelexis Biosciences for projects unrelated to this work. MK is in the advisory board of AbbVie, Auxenion GmbH, Dark Blue Therapeutics, Legend Biotech, MEI Pharma, Menarini\/Stemline Therapeutics, Novartis, Servier, Syndax, Vincerx and consulting for AbbVie, Adaptive, AmMax, AstraZeneca, Curis, Janssen, Kyowa Kirin, Menarini\/Stemline Therapeutics, Mitsubishi Tanabe Pharma American, Sanofi Aventis, Servier. MK has received research funding from AbbVie, Janssen, Klondike Biopharma. KG received research funding from Ionctura, SA and ADC Therapeutics. IM reports participation in advisory board with Ascentage Pharma. AECOM Stem Cell Isolation and Xenotransplantation Facility is funded through New York Stem Cell Science grant no. C029154, Analytical Imaging Facility is funded through NCI cancer center support grant P30CA013330 and shared instrument grant JEOL 1400Plus TEM: SIG #1S10OD016214-01A1, Einstein FACS Core Facility is supported by NIH grants - P30CA013330 and shared instruments grants S10OD026833 and S10OD032169. We also acknowledge the availability of Leica Stellaris 8 Confocal Microscope (1S10OD034397-01) in the shared facility of Albert Einstein College of Medicine.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. Murine experiments were performed in accordance with the protocol (#00001526) approved by the Institutional Animal Care and Use Committee at Albert Einstein College of Medicine (AECOM). AML patient samples were obtained from an IRB approved biobank (#2005-536) at the Albert Einstein College of Medicine.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}