{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T05:06:29Z","timestamp":1779080789736,"version":"3.51.4"},"reference-count":155,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Graduate Studies and Scientific Research at the University of Bisha"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Clonal evolution, genetic heterogeneity, and impaired myeloid differentiation are characteristics of acute myeloid leukemia (AML), an aggressive hematologic malignancy. Many patients continue to have poor outcomes even after decades of relying on aggressive induction chemotherapy (7\u202f+\u202f3 regimen), particularly those who are elderly or have unfavorable molecular characteristics. Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) were effective treatments for acute promyelocytic leukemia (APL) which changed the therapeutic paradigm from cytotoxicity to maturation-based methods. More recently, differentiation therapy has been expanded to include other AML subtypes since IDH inhibitors were developed, (enasidenib, ivosidenib) and menin inhibitors (revumenib, ziftomenib). Meanwhile, epigenetic modulators like azacitidine emphasize the wider therapeutic impact of reversing transcriptional and metabolic blocks. Biomarker-driven stratification is now possible thanks to advancements in genomic profiling, which enhances the selection of patients who stand to gain the most from differentiation-based strategies. In addition to summarizing important therapeutic drugs and trial results, this review incorporates the most recent research on the molecular basis of differentiation arrest and looks at issues including resistance, relapse, and the absence of prognostic biomarkers. Differentiation therapy is a mechanistically sound and less harmful approach that supports targeted therapy and has the potential to redefine AML treatment by reestablishing normal hematopoietic development.<\/jats:p>","DOI":"10.3389\/fmed.2026.1818483","type":"journal-article","created":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T04:17:55Z","timestamp":1779077875000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Differentiation therapy in acute myeloid leukaemia: molecular basis, clinical progress, and future perspectives"],"prefix":"10.3389","volume":"13","author":[{"given":"Abdulaziz","family":"Asiri","sequence":"first","affiliation":[{"name":"Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha","place":["Bisha, Saudi Arabia"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"6285","DOI":"10.1200\/JCO.2005.05.010","article-title":"Genetics of myeloid malignancies: Pathogenetic and clinical implications","volume":"23","author":"Fr\u00f6hling","year":"2005","journal-title":"J Clin Oncol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"3481","DOI":"10.1182\/blood-2005-09-3724","article-title":"Age and acute myeloid leukemia","volume":"107","author":"Appelbaum","year":"2006","journal-title":"Blood"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2720","DOI":"10.1002\/cncr.28129","article-title":"Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over three 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