{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:36:44Z","timestamp":1789774604010,"version":"4.0.1"},"reference-count":57,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute myeloid leukemia (AML) is characterized by differentiation arrest, driving blast proliferation, and abnormal blood formation. While differentiation therapy revolutionized acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), its extension into non-APL AML has been limited until recent targeted agents. This narrative review synthesizes preclinical and clinical evidence into differentiation-inducing therapy, with a focus on IDH1\/2, FLT3 and menin inhibitors. Following SANRA guidelines, we searched PubMed (2010\u2013September 2025) for clinical trials and key preclinical studies, with particular attention to the molecular mechanism of differentiation induction, clinical efficacy, and the management of differentiation syndrome (DS). IDH1\/2 inhibitors (ivosidenib, enasidenib, olutasidenib) yield overall response rates (ORRs) of 30\u201394% in AML with DS in 10\u201319%. Menin inhibitors (revumenib, ziftomenib, enzomenib, bleximenib) achieve ORRs of 33\u201388% in KMT2A-rearranged or NPM1-mutated AML, with DS in 10\u201325% and QT prolongation as key toxicities. FLT3 inhibitors (gilteritinib, quizartinib) improve survival in FLT3-mutated AML with DS in 1\u20135%. Resistance mutations limit durability and combinations enhance efficacy. Differentiation therapy represents a paradigm shift towards non-cytotoxic AML management. Improved recognition of DS and rational combination approaches will be essential to maximize the therapeutic benefit. Future research should address mechanisms of resistance and biomarkers to achieve cures beyond APL.<\/jats:p>","DOI":"10.3390\/ijms27041775","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:05:46Z","timestamp":1770897946000},"page":"1775","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Differentiation Syndrome in Acute Myeloid Leukemia: Molecular Mechanisms, Clinical Spectrum, and Emerging Therapeutic Paradigms"],"prefix":"10.3390","volume":"27","author":[{"given":"Razan","family":"Mansour","sequence":"first","affiliation":[{"name":"Department of Hematology and Medical Oncology, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8661-9006","authenticated-orcid":false,"given":"Abeer","family":"Yaseen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2959-1177","authenticated-orcid":false,"given":"Zaid","family":"Abdel Rahman","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, King Hussein Cancer Center, Amman 11941, Jordan"},{"name":"School of Medicine, University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1002\/gcc.22756","article-title":"Clonal hematopoiesis and preleukemia-Genetics, biology, and clinical implications","volume":"58","author":"Hartmann","year":"2019","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1053\/j.seminhematol.2018.08.001","article-title":"Genetic and epigenetic determinants of AML pathogenesis","volume":"56","author":"Cai","year":"2019","journal-title":"Semin. 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Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1775\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:10:44Z","timestamp":1770898244000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1775"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":57,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041775"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041775","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]}}}