{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:21:00Z","timestamp":1778145660379,"version":"3.51.4"},"posted":{"date-parts":[[2025,5,22]]},"group-title":"Cancer Biology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"DOI":"10.13039\/501100001459","name":"Ministry of Education (MOE), Singapore","doi-asserted-by":"crossref","award":["MOE-000573-00"],"award-info":[{"award-number":["MOE-000573-00"]}],"id":[{"id":"10.13039\/501100001459","id-type":"DOI","asserted-by":"crossref"}]},{"name":"NUS-Paris University Joint Grant"},{"DOI":"10.13039\/501100001352","name":"National University of Singapore","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001352","id-type":"DOI","asserted-by":"crossref"}]},{"name":"EMBO"},{"name":"SINGA"},{"name":"ERC CoG","award":["DynAML, 101088563"],"award-info":[{"award-number":["DynAML, 101088563"]}]},{"name":"LNCC","award":["EL2024-PUISSANT"],"award-info":[{"award-number":["EL2024-PUISSANT"]}]},{"DOI":"10.13039\/501100005677","name":"Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"crossref","award":["project DJCLS 07 R\/2024"],"award-info":[{"award-number":["project DJCLS 07 R\/2024"]}],"id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Deutsche Forschungsgesellschaft","award":["DFG KR 3886\/8-1"],"award-info":[{"award-number":["DFG KR 3886\/8-1"]}]},{"name":"Deutsche Konsortium f\u00fcr Translationale Krebsforschung"},{"name":"Leukemia Research Foundation New Investigator Research Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>TP53<\/jats:italic>\n                  mutations across multiple cancers, including acute myeloid leukemia (AML), are associated with poor outcomes irrespective of treatment modality. However, druggable vulnerabilities beyond canonical p53 targets remain largely unexplored. We identify\n                  <jats:italic>BIRC5<\/jats:italic>\n                  (encodes survivin), an inhibitor of the apoptosis protein (IAP) family, as a novel vulnerability in\n                  <jats:italic>TP53<\/jats:italic>\n                  mutant AML using an unbiased, comprehensive multiomics approach \u2014 whole-genome CRISPR knockout screen, bulk and single-cell RNA-seq, proteomics, and high-throughput drug screen. Mechanistically,\n                  <jats:italic>BIRC5<\/jats:italic>\n                  deletion in AML restored caspase-9 and -3\/7 activity and downregulated other IAPs, implicating\n                  <jats:italic>BIRC5<\/jats:italic>\n                  as the central post-mitochondrial regulator for blocking apoptosis. p53 stabilization suppressed\n                  <jats:italic>BIRC5<\/jats:italic>\n                  selectively in\n                  <jats:italic>TP53<\/jats:italic>\n                  wild-type AML, explaining\n                  <jats:italic>BIRC5<\/jats:italic>\n                  upregulation in\n                  <jats:italic>TP53<\/jats:italic>\n                  mutant lines and AML primary tumors (n &gt; 700). Longitudinal single-cell RNAseq (n = 22 pairs) revealed expansion of\n                  <jats:italic>\n                    BIRC5\n                    <jats:sup>high<\/jats:sup>\n                  <\/jats:italic>\n                  stem and progenitor leukemia clones in\n                  <jats:italic>TP53<\/jats:italic>\n                  mutant AML patients post-VenAza therapy. Survivin and IAP inhibitors emerged as top combination partners with VenAza in\n                  <jats:italic>TP53<\/jats:italic>\n                  mutant AML cells and showed potent\n                  <jats:italic>in vivo<\/jats:italic>\n                  leukemic blast inhibition in cell line and patient-derived xenograft models along with primary tumors. Beyond AML,\n                  <jats:italic>BIRC5<\/jats:italic>\n                  was upregulated broadly across 17 of 25\n                  <jats:italic>TP53<\/jats:italic>\n                  mutant cancers in the TCGA cohort, and combination with survivin inhibitors overcame chemotherapy resistance in\n                  <jats:italic>TP53<\/jats:italic>\n                  deficient triple negative breast and colorectal cancers. These findings define\n                  <jats:italic>BIRC5<\/jats:italic>\n                  as a critical, targetable dependency and unveil survivin\/IAP inhibition as a promising therapeutic axis to overcome p53-related resistance across both hematologic and solid malignancies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key Points<\/jats:title>\n                  <jats:list list-type=\"order\">\n                    <jats:list-item>\n                      <jats:p>BIRC5 upregulation is a novel dependency in TP53 mutant AML that mediates therapy resistance by evasion of apoptosis.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Combination with Survivin\/IAP inhibitors overcomes venetoclax\/azacitidine resistance in TP53 mutant AML.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.17.654633","type":"posted-content","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T08:45:19Z","timestamp":1747903519000},"source":"Crossref","is-referenced-by-count":2,"title":["<i>BIRC5<\/i>\n                  dependency defines a targetable vulnerability in\n                  <i>TP53<\/i>\n                  mutant acute myeloid leukemia"],"prefix":"10.64898","author":[{"given":"Ahmed M.","family":"Mamdouh","sequence":"first","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore"},{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Horus University \u2013 Egypt, New Damietta 34518, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang Qi","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, 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