{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:59:03Z","timestamp":1785437943215,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,15]]},"group-title":"Molecular Biology","reference-count":59,"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":[{"award":["R01GM078455"],"award-info":[{"award-number":["R01GM078455"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Leukemia and Lymphoma Society"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>The histone demethylase KDM1A (LSD1), a component of the CoREST corepressor complex, is highly expressed in hematologic malignancies and regulates hematopoietic differentiation. Despite its essential developmental role, LSD1 inhibition has emerged as a promising strategy to enhance retinoic acid (RA)-responsive gene expression in subsets of acute myeloid leukemia (AML). Here, we show that LSD1 physically interacts with RAR\/RXR heterodimers at specific genomic loci, restricting chromatin accessibility and transcriptional activation of differentiation programs. Single-agent inhibition of LSD1 or HDACs promotes only partial differentiation. In contrast, Corin, a dual LSD1\/CoREST inhibitor, synergizes with all-trans retinoic acid (ATRA) to induce robust myeloid differentiation and apoptosis. Corin treatment alone does not significantly increase H3K4me3 levels; however, in combination with ATRA, it disrupts CoREST-RAR\/RXR complexes and facilitates the recruitment of the coactivator p300. Together, they shift chromatin to an active state, enhancing H3K4me3 via increased transcriptional engagement and coactivator recruitment. Our findings identify the functional antagonism between CoREST and p300 as a regulatory axis of RA signaling in AML. Targeting this mechanism with Corin and ATRA re-sensitizes non-APL AML cells to RA-induced differentiation, suggesting a broader therapeutic approach for overcoming resistance in ATRA-refractory leukemias.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Co-inhibition of LSD1 and HDACs with Corin, combined with ATRA, reprograms chromatin by replacing CoREST with p300, uniquely activating differentiation-associated genes and offering a targeted strategy for treating AML.\n                    <jats:italic>Graphical abstract created with BioRender<\/jats:italic>\n                    (\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/biorender.com\">https:\/\/biorender.com<\/jats:ext-link>\n                    <jats:italic>)<\/jats:italic>\n                    .\n                  <\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"682235v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.10.13.682235","type":"posted-content","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T14:10:15Z","timestamp":1760537415000},"source":"Crossref","is-referenced-by-count":0,"title":["Balancing Activation and Repression: CoREST-p300 Antagonism Controls Retinoic Acid-Driven Differentiation in 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 Gomes Dos","family":"Santos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadat","family":"Dokaneheifard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel D.","family":"Whedon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Valencia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikumar","family":"Arigela","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"}]},{"given":"Justin M.","family":"Watts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip A.","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramin","family":"Shiekhattar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101710200561000_2025.10.13.682235v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2661"},{"key":"2025101710200561000_2025.10.13.682235v1.2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-4054"},{"issue":"3","key":"2025101710200561000_2025.10.13.682235v1.3","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/s41375-020-0892-z","article-title":"A proof of concept phase I\/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory\/relapsed AML patients not eligible for intensive therapy","volume":"35","year":"2021","journal-title":"Leukemia"},{"key":"2025101710200561000_2025.10.13.682235v1.4","unstructured":"Kruszewski, M. , et al., Sensitization of Non-M3 Acute Myeloid Leukemia Blasts to All-Trans Retinoic Acid by the LSD1 Inhibitor Tranylcypromine: TRANSATRA Phase I Study. 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