{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:16:42Z","timestamp":1790612202708,"version":"4.1.0"},"reference-count":78,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"48","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Adv."],"published-print":{"date-parts":[[2023,12,1]]},"abstract":"<jats:p>\n                    The tumor suppressor\n                    <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                    is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2\/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets.\n                    <jats:italic toggle=\"yes\">TP53<\/jats:italic>\n                    regulates\n                    <jats:italic toggle=\"yes\">MYC<\/jats:italic>\n                    , and MDM2\/XPO1 inhibition disrupted the c-MYC\u2013regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2\/XPO1 inhibition in vivo. However, AML cells persisting after MDM2\/XPO1 inhibition exhibit a quiescence- and stress response\u2013associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adh1436","type":"journal-article","created":{"date-parts":[[2023,11,29]],"date-time":"2023-11-29T14:00:24Z","timestamp":1701266424000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":38,"title":["Enhanced\n                    <i>TP53<\/i>\n                    reactivation disrupts\n                    <i>MYC<\/i>\n                    transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias"],"prefix":"10.1126","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5827-7406","authenticated-orcid":true,"given":"Yuki","family":"Nishida","sequence":"first","affiliation":[{"name":"Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson 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