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Although standard induction regimens based on anthracyclines often achieve initial remission, up to 25% of patients exhibit primary refractory disease and nearly 50% relapse, underscoring the urgent need to overcome therapy resistance. Aldehyde dehydrogenase 1 (ALDH1) contributes to leukemic cell survival by maintaining stemness, proliferation, and chemoresistance through aldehyde detoxification and retinoic acid synthesis. Here, we identify two enhancer elements, ALDH1A1\u2010E3 and ALDH1A2\u2010E1\u2010A, that mediate transcriptional activation of\n                    <jats:italic>ALDH1A1<\/jats:italic>\n                    and\n                    <jats:italic>ALDH1A2<\/jats:italic>\n                    in response to the anthracycline daunorubicin. These enhancers are regulated by STAT3 and FOS\/JUN transcription factors, which cooperatively link drug response to ALDH1 induction. Functional validation in AML cell lines, primary samples, and xenograft models shows that ALDH1 upregulation is part of an adaptive stress response and may contribute to reduced anthracycline sensitivity. Co\u2010treatment with the ALDH1A1\/1A2 inhibitor DIMATE synergistically enhances daunorubicin efficacy across in vitro and in vivo resistant models. Consistently, high\n                    <jats:italic>ALDH1<\/jats:italic>\n                    expression is associated with adverse genetic risk, prior anthracycline exposure, and inferior OS, particularly in relapsed\/refractory AML. These findings uncover a novel enhancer\u2010mediated mechanism of ALDH1 induction in the context of anthracycline exposure and support the rationale for future clinical trials combining standard treatments with ALDH1\u2010targeted approaches, including the clinical\u2010stage inhibitor DIMATE.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70244","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T16:46:01Z","timestamp":1761669961000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Upregulation of ALDH1 as an adaptive epigenetic response to anthracyclines in acute myeloid leukemia"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0831-260X","authenticated-orcid":false,"given":"Francesco","family":"Leonetti","sequence":"first","affiliation":[{"name":"Advanced BioDesign Saint Priest France"},{"name":"INSERM, TAGC, UMR1090 Aix\u2010Marseille 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