Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.

Abstract

BACKGROUND:

Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type.

METHODS:

IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC-MS, GC-MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms.

RESULTS:

We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo.

CONCLUSIONS:

Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.

• Authors: Peiting Zeng, Wenhua Lu, Jingyu Tian, Shuang Qiao, Jiangjiang Li, Christophe Glorieux, Shijun Wen, Hui Zhang, Yiqing Li, Peng Huang
• Journal: Journal of hematology & oncology (J Hematol Oncol) Vol. 15 Issue 1 Pg. 30 (03 21 2022) ISSN: 1756-8722 [Electronic] England
• PMID: 35313945 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Lipids
• Citric Acid
• Isocitrate Dehydrogenase

Topics

• Animals
• Catalysis
• Citric Acid (therapeutic use)
• Humans
• Isocitrate Dehydrogenase (genetics, metabolism)
• Leukemia, Myeloid, Acute (drug therapy, genetics)
• Lipids (therapeutic use)
• Mice
• Mutation