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This dependency is most evident in KMT2A\u2010rearranged and NPM1\u2010mutated acute myeloid leukemia (AML), but also extends to other HOX\u2010dependent entities, including leukemias with NUP98 rearrangements and UBTF tandem duplications, broadening the therapeutic relevance of menin inhibition. Menin acts as a central scaffold within chromatin\u2010associated complexes that maintain expression of HOXA cluster genes and MEIS1, integrating signals from epigenetic regulators and lineage\u2010specific transcription factors. Disruption of the menin\u2013KMT2A interaction results in transcriptional reprogramming, induction of differentiation, and loss of leukemic stem cell properties, providing a strong mechanistic rationale for therapeutic targeting. This review synthesizes current knowledge on the molecular basis of menin dependency, with emphasis on structural insights, transcriptional circuitry, and lineage plasticity. We critically evaluate the preclinical and clinical development of menin inhibitors, including revumenib, ziftomenib, bleximinib, and icovamenib, summarizing efficacy signals in relapsed\/refractory disease, safety profiles, and emerging resistance mechanisms. Special attention is given to combination strategies with venetoclax, FLT3 inhibitors, chemotherapy, and epigenetic agents, which aim to enhance response durability and mitigate resistance. Finally, we discuss ongoing clinical trials, unresolved challenges in patient selection and sequencing, and future directions for integrating menin inhibition into precision\u2010based treatment paradigms for acute leukemia.<\/jats:p>","DOI":"10.1111\/ejh.70186","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T07:50:37Z","timestamp":1775116237000},"page":"132-143","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting the Menin\u2013\n                    <scp>KMT2A<\/scp>\n                    Axis in Acute Leukemia: From Epigenetic Dependency to Clinical Translation"],"prefix":"10.1111","volume":"117","author":[{"given":"Antonella","family":"Bruzzese","sequence":"first","affiliation":[{"name":"Hematology Unit, Department of Onco\u2010Hematology AO of Cosenza  Cosenza 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