{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:54:34Z","timestamp":1792652074538,"version":"4.5.0"},"posted":{"date-parts":[[2025,3,27]]},"group-title":"Cancer Biology","reference-count":22,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,27]],"date-time":"2025-03-27T00:00:00Z","timestamp":1743033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,3,27]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Acute myeloid leukemia (AML) is a heterogeneous cancer that is associated with poor outcomes. Revumenib and other menin inhibitors have shown promising activity against AMLs with\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -rearrangements or\n                  <jats:italic>NPM1<\/jats:italic>\n                  mutations. However, mechanisms of\n                  <jats:italic>de novo<\/jats:italic>\n                  resistance have not yet been elucidated. We analyzed a panel of cell lines and generated an isogenic model to assess the impact of\n                  <jats:italic>TP53<\/jats:italic>\n                  mutations on the response of AML cells to revumenib.\n                  <jats:italic>TP53<\/jats:italic>\n                  mutations are associated with\n                  <jats:italic>de novo<\/jats:italic>\n                  resistance to revumenib, impaired induction of\n                  <jats:italic>TP53<\/jats:italic>\n                  transcriptional targets, and deregulated expression of the BH3 proteins BCL-2 and MCL-1. The MCL-1 inhibitor MIK665, but not venetoclax, preferentially sensitized\n                  <jats:italic>TP53<\/jats:italic>\n                  -mutant AML cells to revumenib. These data identify mutant\n                  <jats:italic>TP53<\/jats:italic>\n                  as a potential biomarker for\n                  <jats:italic>de novo<\/jats:italic>\n                  resistance to revumenib, and provide a rationale to evaluate MCL-1 and menin inhibitor combinations in patients\n                  <jats:italic>KMT2A<\/jats:italic>\n                  -rearranged leukemias with\n                  <jats:italic>TP53<\/jats:italic>\n                  mutations.\n                <\/jats:p>","DOI":"10.1101\/2025.03.24.644993","type":"posted-content","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T03:39:33Z","timestamp":1743133173000},"source":"Crossref","is-referenced-by-count":3,"title":["<i>TP53<\/i>\n                  Inactivation Confers Resistance to the Menin Inhibitor Revumenib in Acute Myeloid Leukemia"],"prefix":"10.64898","author":[{"given":"Jeevitha","family":"D\u2019Souza","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille J.","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya C.","family":"Ballapuram","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail S.","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa Rane","family":"Batingana","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam J.","family":"Lamble","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Seattle Children\u2019s Hospital, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhonda E.","family":"Ries","sequence":"additional","affiliation":[{"name":"Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina E.","family":"Morales","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charisa","family":"Cottonham","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranav","family":"Gona","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotu","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Shannon","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheil","family":"Meshinchi","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Seattle Children\u2019s Hospital, Seattle, WA, USA"},{"name":"Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin S.","family":"Braun","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041201080304000_2025.03.24.644993v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.09.025"},{"key":"2026041201080304000_2025.03.24.644993v1.2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.172783"},{"key":"2026041201080304000_2025.03.24.644993v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.258186"},{"key":"2026041201080304000_2025.03.24.644993v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.773"},{"key":"2026041201080304000_2025.03.24.644993v1.5","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-05-429274"},{"key":"2026041201080304000_2025.03.24.644993v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.02.016"},{"key":"2026041201080304000_2025.03.24.644993v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05812-3"},{"key":"2026041201080304000_2025.03.24.644993v1.8","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2020-142003"},{"key":"2026041201080304000_2025.03.24.644993v1.9","doi-asserted-by":"crossref","first-page":"4318","DOI":"10.1182\/blood-2021-148045","article-title":"Novel 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