{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T21:10:10Z","timestamp":1794258610977,"version":"4.9.0"},"reference-count":56,"publisher":"American Society of Hematology","issue":"21","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,20]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>TP53-Y220C is a recurrent hot spot mutation in cancers and leukemias. It is observed predominantly in acute myeloid leukemia (AML)\/myelodysplastic syndromes among hematological malignancies and is associated with poor outcome. The mutation creates a structural pocket in the p53 protein. PC14586 (rezatapopt) is a small molecule designed to bind to this pocket and thus restore a p53 wild-type (p53-WT) conformation. We demonstrate that PC14586 converts p53-Y220C into a p53-WT conformation and activates p53 transcriptional targets but surprisingly induces limited\/no apoptosis in TP53-Y220C AML. Mechanistically, MDM2 induced by PC14586-activated conformational p53-WT and the nuclear exporter exportin 1 (XPO1) reduce the transcriptional activities of p53, which are fully restored by inhibition of MDM2 and\/or XPO1. Importantly, p53-WT protein can bind to B-cell lymphoma 2 (BCL-2), competing with BCL-2-associated X protein (BAX) in the BH3 binding pocket of BCL-2, and also binds to BCL-xL and myeloid cell leukemia 1 (MCL-1). However, such binding by PC14586-activated conformational p53-WT is not detected. Pharmacological inhibition of the BCL-2\/BAX interaction with venetoclax fully compensates for this deficiency, induces massive cell death in AML cells and stem\/progenitor cells in vitro, and prolongs survival of TP53-Y220C AML xenografts in vivo. Collectively, we identified transcription-dependent and -independent mechanisms that limit the apoptogenic activities of reactivated conformational p53-WT and suggest approaches to optimize apoptosis induction in TP53-mutant leukemia. A clinical trial of PC14586 in TP53-Y220C AML\/myelodysplastic syndromes has recently been initiated. This trial was registered at www.ClinicalTrials.gov as #NCT06616636.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2025028935","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T13:57:18Z","timestamp":1751551038000},"page":"2574-2588","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":16,"title":["Restoring p53 wild-type conformation in\n                    <i>TP53<\/i>\n                    -Y220C\u2013mutant acute myeloid leukemia"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0076-0889","authenticated-orcid":false,"given":"Bing Z.","family":"Carter","sequence":"first","affiliation":[{"name":"1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po Yee","family":"Mak","sequence":"additional","affiliation":[{"name":"1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1321-0114","authenticated-orcid":false,"given":"Edward","family":"Ayoub","sequence":"additional","affiliation":[{"name":"1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4373-6926","authenticated-orcid":false,"given":"Xiaogang","family":"Wu","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baozhen","family":"Ke","sequence":"additional","affiliation":[{"name":"1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Nishida","sequence":"additional","affiliation":[{"name":"1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Futreal","sequence":"additional","affiliation":[{"name":"2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3330-2174","authenticated-orcid":false,"given":"Lauren 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