{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:03:28Z","timestamp":1785776608936,"version":"3.56.0"},"reference-count":40,"publisher":"American Society for Clinical Investigation","issue":"5","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":41,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Cancer Institute","award":["1R01 CA136537-01"],"award-info":[{"award-number":["1R01 CA136537-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,9]]},"abstract":"<jats:p>\n                    The survival of patients with acute myelogenous leukemia (AML) carrying mutations in\n                    <jats:italic>TP53<\/jats:italic>\n                    is dismal. We report the results of a detailed characterization of responses to treatment ex vivo with the MDM2 inhibitor MI219, a p53 protein stabilizer, in AML blasts from 165 patients focusing analyses on patients with WT\n                    <jats:italic>TP53<\/jats:italic>\n                    . In total 33% of AML were absolute resistant to MDM2 inhibitor\u2013induced apoptosis, of which 45% carried\n                    <jats:italic>TP53<\/jats:italic>\n                    mutation and 55% were\n                    <jats:italic>TP53<\/jats:italic>\n                    WT. We conducted array-based expression profiling of 10 resistant and ten sensitive AML cases with WT\n                    <jats:italic>TP53<\/jats:italic>\n                    status, respectively, at baseline and after 2 hours and 6 hours of MDM2 inhibitor treatment. While sensitive cases showed the induction of classical TP53 response genes, this was absent or attenuated in resistant cases. In addition, the sensitive and resistant AML samples at baseline profoundly differed in the expression of inflammation-related and mitochondrial genes. No patient with\n                    <jats:italic>TP53<\/jats:italic>\n                    mutated AML survived. The 4-year survival of AML with defective MDM2 inhibitor\u2013induced TP53-mediated apoptosis despite WT\n                    <jats:italic>TP53<\/jats:italic>\n                    was dismal, at 19% when\n                    <jats:italic>NPM1<\/jats:italic>\n                    was comutated and 6% when\n                    <jats:italic>NPM1<\/jats:italic>\n                    was WT. In summary, we identified prevalent multicausal defects in TP53-mediated apoptosis in AML resulting in extremely poor patient survival.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.197261","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T18:35:56Z","timestamp":1769538956000},"source":"Crossref","is-referenced-by-count":1,"title":["Patients with AML with WT TP53 but defective TP53-mediated apoptosis have a dismal survival"],"prefix":"10.1172","volume":"11","author":[{"given":"Josephine","family":"Dubois","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology and Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Palmer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren","family":"King","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology and Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Rizk","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology and Oncology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-738X","authenticated-orcid":true,"given":"Karan","family":"Bedi","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerby A.","family":"Shedden","sequence":"additional","affiliation":[{"name":"Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7734-4387","authenticated-orcid":true,"given":"Sami N.","family":"Malek","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hematology and Oncology,"},{"name":"Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.9.3148.3148"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1516192"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-266999"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2021014472"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-0921"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0708917105"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.11.002"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.1092472"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1021\/jm051122a"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.050"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/387296a0"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/387299a0"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.274.5289.948"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.11.8596"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.4161\/cc.8.11.8746"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.046904"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-12-5148"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2005-02-0553"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.04.037"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-01-261628"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ncb814"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2008.211"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024028239"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00480-0"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0956"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.502"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.169"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.40.6652"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601292"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2451"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-02-763086"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2016.350"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2024024968"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2058"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-3105"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/4.2.249"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/197261\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T19:28:35Z","timestamp":1778873315000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/197261"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,1,27]]},"published-print":{"date-parts":[[2026,3,9]]}},"alternative-id":["10.1172\/jci.insight.197261"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.197261","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"article-number":"e197261"}}