{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:37:00Z","timestamp":1785411420517,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Cancer Biology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01GM078455"],"award-info":[{"award-number":["R01GM078455"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["P30CA240139"],"award-info":[{"award-number":["P30CA240139"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009447","name":"Leukemia & Lymphoma Society of Canada","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100009447","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Acute myeloid leukemia (AML) harboring\n                  <jats:italic>MLL<\/jats:italic>\n                  (\n                  <jats:italic>MLL1, KMT2A<\/jats:italic>\n                  ) rearrangement (\n                  <jats:italic>MLL-r<\/jats:italic>\n                  ) remains a lethal subtype with limited durable responses to single-agent menin inhibition. To define rational combination strategies, we performed a high-throughput screen of &gt;900 epigenetic modulators in combination with menin inhibition in\n                  <jats:italic>MLL-r<\/jats:italic>\n                  AML models. This uncovered consistent synergy between menin and lysine-specific demethylase 1 (LSD1) inhibition, including with the clinical agent iadademstat. Mechanistically, LSD1 was found to interact with LEDGF\/p75 (PSIP1), a chromatin-anchoring cofactor of the menin-MLL complex at H3K36me3 marked euchromatin. Chromatin profiling revealed extensive co-occupancy of LSD1 and menin-MLL components at leukemogenic loci in MLL-r AML cells. Dual inhibition of menin and LSD1 dismantled this chromatin complex, evicted H3K36me3 from LEDGF-bound sites, and reprogrammed transcription toward myeloid differentiation. Combined menin and LSD1 blockade repressed canonical MLL targets, including\n                  <jats:italic>HOXA9, MYC, FLT3, PBX3<\/jats:italic>\n                  , and\n                  <jats:italic>CDK6<\/jats:italic>\n                  , while restoring H3K36me3 and H3K4me3 and activating differentiation-associated genes. In vivo, the combination produced potent antileukemic effects in both MOLM-13 and\n                  <jats:italic>MLL-r<\/jats:italic>\n                  patient-derived xenografts, markedly reducing leukemic burden and extending survival without overt toxicity. These findings identify LSD1 as a critical cofactor of the menin-MLL-LEDGF axis and establish concurrent menin and LSD1 inhibition as a mechanistically informed combinatorial therapeutic approach in\n                  <jats:italic>MLL-r<\/jats:italic>\n                  AML.\n                <\/jats:p>","DOI":"10.1101\/2025.10.13.681683","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T14:25:16Z","timestamp":1760538316000},"source":"Crossref","is-referenced-by-count":1,"title":["Co-targeting menin and LSD1 dismantles oncogenic programs and restores differentiation in MLL-rearranged AML"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3521-8782","authenticated-orcid":false,"given":"Mina M.","family":"Tayari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9671-4272","authenticated-orcid":false,"given":"Helena","family":"Gomes Dos Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6735-6851","authenticated-orcid":false,"given":"Felipe","family":"Beckedorff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4262-4458","authenticated-orcid":false,"given":"Tulasigeri","family":"Totiger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5110-4518","authenticated-orcid":false,"given":"Adnan","family":"Mookhtiar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Lesley","family":"Kingham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-354X","authenticated-orcid":false,"given":"Guilherme Miura","family":"Lavezzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0730-3541","authenticated-orcid":false,"given":"Gloria","family":"Mas 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