Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.

ABSTRACT: Acute myeloid leukemia with mutations in TP53 (TP53^mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53^mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53^mut AML cell lines and primary samples, we determined that TP53^mut 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 TP53^mut AML. The geranylgeranyl pyrophosphate (GGPP) branch

SUBMITTER: Skuli SJ 

PROVIDER: S-EPMC12380605 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature