{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T11:36:23Z","timestamp":1789212983572,"version":"build-2803163510"},"reference-count":49,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T00:00:00Z","timestamp":1780099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health Institute","award":["R03CA249562"],"award-info":[{"award-number":["R03CA249562"]}]},{"name":"Whitehead Scholar Award from Duke University School of Medicine"},{"id":[{"id":"https:\/\/ror.org\/00py81415","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>APR-246 (Eprenetapopt) is a small-molecule drug that restores the activity of dysfunctional p53 proteins caused by missense mutations that affect the DNA-binding domain. However, recent studies suggest that APR-246 can also induce cell death in cancer cells that carry wild-type (WT) TP53. Here, we aimed to determine the impact of APR-246 on the survival of acute myeloid leukemia (AML) cells using isogenic Molm13 cells that harbor WT TP53, a missense mutation of TP53R175H, or a biallelic deletion of TP53 (TP53\u2212\/\u2212). Our results showed that Molm13 TP53\u2212\/\u2212 cells were significantly more resistant to APR-246-induced cell death compared with their Molm13 TP53R175H\/\u2212 mutant and Molm13 TP53+\/+ counterparts. In addition, knockdown of TP53 significantly reduced cytotoxicity induced by APR-246 in two TP53 WT AML cell lines (MV4-11 and OCI-AML2). Moreover, APR-246 markedly decreased the clonogenicity of TP53 WT hematopoietic stem\/progenitor cells (HSPCs) isolated from humans and mice. In contrast, biallelic loss of TP53, but not TP53 missense mutation, significantly increased the resistance of mouse HSPCs to APR-246. Mechanistically, the loss of functional p53 proteins in Molm13 and MV4-11 cells decreased intrinsic apoptosis and impaired the production of cellular reactive oxygen species (ROS) induced by APR-246. Together, our results indicate that, in at least a subset of AML cell lines and normal HSPCs, APR-246-induced ROS production and cytotoxicity are enhanced in the presence of WT p53 proteins.<\/jats:p>","DOI":"10.3390\/ijms27114974","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T12:45:08Z","timestamp":1780404308000},"page":"4974","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Wild-Type p53 Protein Enhances APR-246-Induced Cytotoxicity in Acute Myeloid Leukemia and Normal Hematopoietic Stem\/Progenitor Cells"],"prefix":"10.3390","volume":"27","author":[{"given":"John B.","family":"Cart","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"},{"name":"Department of Pathology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Norris","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadhna O.","family":"Piryani","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Chan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Eyler","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0673-633X","authenticated-orcid":false,"given":"Chang-Lung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Duke University School of Medicine, Durham, NC 27708, USA"},{"name":"Department of Pathology, Duke University School of Medicine, Durham, NC 27708, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,30]]},"reference":[{"key":"ref_1","unstructured":"Vakiti, A., Reynolds, S.B., and Mewawalla, P. 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