Chemoresistance of TP53 mutant AML requires the mevalonate byproduct, GGPP, for induction of an adaptive stress response

Acute myeloid leukemia with mutations in TP53 (TP53mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53mut AML cell lines and primary samples, we determined that TP53mut 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 TP53mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating one-carbon metabolism and subsequent glutathione and polyamine synthesis for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53mut 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 TP53mut AML Overall design: RNA-seq profiling of purified leukemic blasts from acute myeloid leukemia patients at diagnosis. Patients were stratified based on outcome and TP53 mutation status.