Skuli Sarah J, Bakayoko A'ishah, Kruidenier Marisa, Manning Bryan, Pammer Paige, Salimov Akmal, Riley Owen, Brake-Sillá Gisela, Dopkin Derrick, Bowman Michael, Martinez-Gutierrez Leslie N, Anderson Colin C, Reisz Julie A, Buono Roberta, Paul Madhuri, Saland Estelle, Liccardo Francesca, DeVine Ann, Wong Sarah, Xu Jimmy P, Nee Eva, Hausler Ryan, Boettcher Steffen, Sebti Said M, Lai Catherine, Maxwell Kara N, Sarry Jean-Emmanuel, Fruman David A, D'Alessandro Angelo, Mesaros Clementina, Keith Brian, Simon M Celeste, Sung Pamela J, Wertheim Gerald, Skuli Nicolas, Bowman Robert L, Matthews Andrew, Carroll Martin
Division of Hematology & Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Immunology, Microenvironment & Metastasis Program, Ellen and Ronald Caplan Cancer Center, Wistar Institute, Philadelphia, PA, USA.
Leukemia. 2025 Jul 9. doi: 10.1038/s41375-025-02668-6.
Acute myeloid leukemia with mutations in TP53 (TP53 AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53 AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53 AML cell lines and primary samples, we determined that TP53 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 AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53 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 TP53 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 TP53 AML.
携带TP53突变的急性髓系白血病（TP53 AML）预后凶险，中位生存期为6个月。对纯化的AML患者样本进行RNA测序显示，TP53 AML中甲羟戊酸途径基因的表达较高。利用新型的同基因TP53 AML细胞系和原代样本，我们确定TP53 AML对AML化疗药物阿糖胞苷（AraC）的耐药与甲羟戊酸途径活性增加、活性氧（ROS）诱导降低以及线粒体质量和氧化磷酸化增加的线粒体反应相关。用他汀类甲羟戊酸途径抑制剂预处理可逆转这些效应并使TP53 AML对化疗敏感。甲羟戊酸途径的香叶基香叶基焦磷酸（GGPP）分支是TP53 AML化疗耐药所必需的。除了其在线粒体生物发生中的作用外，我们还发现了GGPP在调节谷胱甘肽以应对AraC诱导的ROS方面的新功能。然而，单独使用他汀类药物不足以在体内以及在一项对364例同时接受化疗和他汀类药物治疗TP53 AML患者的回顾性研究中完全逆转化疗耐药。最后，我们确定了成功靶向甲羟戊酸途径的临床情况和策略，特别是为了满足TP53 AML尚未满足的需求。
