{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T02:01:31Z","timestamp":1768528891367,"version":"3.49.0"},"posted":{"date-parts":[[2025,11,11]]},"group-title":"Cancer Biology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T00:00:00Z","timestamp":1762819200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01 CA279317"],"award-info":[{"award-number":["R01 CA279317"]}]},{"name":"NIH","award":["1F31CA281117-01"],"award-info":[{"award-number":["1F31CA281117-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Acute myeloid leukemia (AML) is characterized by differentiation arrest and uncontrolled proliferation. Differentiation therapy aims to treat AML by de-repressing latent myeloid maturation programs to induce cell cycle arrest and subsequent cell death. This approach is curative in the promyelocytic AML subtype, but has met with limited success in other subtypes. Genes such as LSD1 have emerged as intriguing non-APL AML differentiation therapy targets, but results as monoagents in clinical trials have been mixed. Here, we performed differentiation-specific CRISPR screens to identify targets whose inhibition synergizes with LSD1 inhibition to induce terminal differentiation of non-APL AML cells. Intriguingly, the MLL co-factor Menin scored as the top hit. Using cell lines, primary patient samples, and mouse AML models, we find that dual inhibition of LSD1 and Menin is a highly promising approach for differentiation therapy. Mechanistically, we determine that inhibition of Menin downregulates drivers of proliferation and stemness such as MEIS1, and inhibition of LSD1 induces inflammatory and interferon-related pro-myeloid differentiation expression programs. Surprisingly, we find that this combination is effective in selected AML models without mutations in MLL or NPM1, thus nominating dual inhibition of LSD1 and Menin as an attractive therapeutic approach for a mutationally diverse set of non-APL AMLs.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Inhibition of LSD1 and Menin synergizes to induce differentiation of MLL-r and MLL-WT AMLs.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibition of Menin downregulates drivers of proliferation and stemness.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Inhibition of LSD1 induces differentiation-associated inflammatory and interferon responses.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>LSD1 and Menin occupy different areas of the genome.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.09.687496","type":"posted-content","created":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T15:40:22Z","timestamp":1762875622000},"source":"Crossref","is-referenced-by-count":0,"title":["Combinatorial inhibition of LSD1 and Menin induces therapeutic differentiation in AML"],"prefix":"10.64898","author":[{"given":"Mar\u00eda F.","family":"Carrera Rodr\u00edguez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua","family":"Rico","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manaswini","family":"Vijayaraghavan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangxue","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin","family":"King","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ricardo","family":"Petroni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolae Adrian","family":"Leu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haley","family":"Goodrow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathrin","family":"Bernt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerald","family":"McGeehan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4404-2301","authenticated-orcid":false,"given":"M. Andr\u00e9s","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025111309151855000_2025.11.09.687496v1.1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"2025111309151855000_2025.11.09.687496v1.2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1007\/s40291-012-0009-0","article-title":"Molecular-Based Classification of Acute Myeloid Leukemia and Its Role in Directing Rational Therapy","volume":"16","year":"2012","journal-title":"Mol Diagn Ther"},{"key":"2025111309151855000_2025.11.09.687496v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrc989"},{"key":"2025111309151855000_2025.11.09.687496v1.4","first-page":"949","article-title":"All-trans retinoic acid with or without low dose cytosine arabinoside in acute promyelocytic leukemia. 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