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Herein, we show that\n                    <jats:italic>HDAC8<\/jats:italic>\n                    is upregulated in KMT2A-r AML and high HDAC8 is associated with poor overall survival in KMT2A-r AML patients. Using a\n                    <jats:italic>KMT2A::MLLT3<\/jats:italic>\n                    mouse model, we demonstrate that both genetic knockout and pharmacological inhibition of HDAC8 significantly delayed leukemia progression, prolonged survival and reduced disease recurrence. Mechanistically, HDAC8 inhibition downregulates STAT3\u2013MYC axis independent of\n                    <jats:italic>TP53<\/jats:italic>\n                    status across AML genetic subtypes. Biochemical assays revealed that HDAC8 binds directly to STAT3, promoting its deacetylation and stabilization, while HDAC8-selective inhibitor (HDAC8i) treatment results in increased STAT3 acetylation and subsequent STAT3 degradation which in turn downregulates MYC. Given that STAT3\u2013MYC signaling promotes cell survival and Venetoclax resistance, we show that HDAC8i exhibits synergistic anti-leukemia activity with Venetoclax in primary AML cells regardless of\n                    <jats:italic>TP53<\/jats:italic>\n                    status. Combination of HDAC8i and Venetoclax synergistically reduced leukemia burden and significantly prolonged survival in both\n                    <jats:italic>KMT2A::MLLT3<\/jats:italic>\n                    AML and patient-derived xenograft models. This study highlights the regulatory function of HDAC8 on STAT3\u2013MYC and provides the proof-of-principle for targeting HDAC8 in combination with Venetoclax for the treatment of KMT2A-r AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02950-1","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T11:35:12Z","timestamp":1776771312000},"page":"1271-1283","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["HDAC8 inhibition targets STAT3\u2013MYC axis and synergizes with Venetoclax in KMT2A-rearranged acute myeloid leukemia"],"prefix":"10.1038","volume":"40","author":[{"given":"Lianjun","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8955-3010","authenticated-orcid":false,"given":"Wancheng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5917-2961","authenticated-orcid":false,"given":"Yu-Hsuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2338-9365","authenticated-orcid":false,"given":"Dijiong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Chieh","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi-Yang","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Kai","family":"Hua","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5464-0861","authenticated-orcid":false,"given":"Le Xuan Truong","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haojie","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4703-7524","authenticated-orcid":false,"given":"Bin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3983-5908","authenticated-orcid":false,"given":"Guido","family":"Marcucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2595-0419","authenticated-orcid":false,"given":"Ya-Huei","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"2950_CR1","doi-asserted-by":"publisher","first-page":"353","DOI":"10.3324\/haematol.2022.280800","volume":"108","author":"P Stelmach","year":"2023","unstructured":"Stelmach P, Trumpp A. 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