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RNA sequencing on purified AML patient samples showed that <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML had higher expression of mevalonate pathway genes. Using novel, isogenic <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML cell lines and primary samples, we determined that <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of <jats:italic>TP53<\/jats:italic>\n            <jats:sup>mut<\/jats:sup> AML.<\/jats:p>","DOI":"10.1038\/s41375-025-02668-6","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T08:53:08Z","timestamp":1752137588000},"page":"2087-2098","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7711-0732","authenticated-orcid":false,"given":"Sarah 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Competing interests for unrelated studies include the following: CL is a consultant for Bristol Myers Squibb (BMS), AbbVie and Astellas; CL is on advisory boards for Servier, Daiichi, AbbVie, Rigel and Genentech; CL receives research funding from JAZZ and BMS; DAF is a consultant for AbbVie. Other authors declare no relevant competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. All animal-related experiments received ethical approval from the UPenn Institutional Animal Care and Use Committee (IACUC Protocol #803506). The use of deidentified human samples and data collected from the electronic health record received ethical approval from the UPenn and Roswell Park Comprehensive Cancer Center Institutional Review Boards (IRB Protocols #703185 and #BDR173423, respectively). Informed consent was obtained from all participants.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}