Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation

Yifan Chen, Miao Xian, Wenwen Ying, Jiayi Liu, Shaowei Bing, Xiaomin Wang, Jiayi Yu, Xiaojun Xu, Senfeng Xiang, Xuejing Shao, Ji Cao, Qiaojun He, Bo Yang and Meidan Ying ()
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Yifan Chen: Zhejiang University
Miao Xian: Zhejiang University
Wenwen Ying: Zhejiang University
Jiayi Liu: Zhejiang University
Shaowei Bing: Zhejiang University
Xiaomin Wang: Zhejiang University
Jiayi Yu: Zhejiang University
Xiaojun Xu: Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Senfeng Xiang: Zhejiang University
Xuejing Shao: Zhejiang University
Ji Cao: Zhejiang University
Qiaojun He: Zhejiang University
Bo Yang: Zhejiang University
Meidan Ying: Zhejiang University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Drug resistance is vital for the poor prognosis of acute myeloid leukemia (AML) patients, but the underlying mechanism remains poorly understood. Given the unique microenvironment of bone marrow, we reasoned that drug resistance of AML might rely on distinct metabolic processes. Here, we identify succinate dehydrogenase (SDH) deficiency and over-cumulative succinate as typical features in AML, with a marked function in causing the resistance of AML cells to various anti-cancer therapies. Mechanistically, succinate promotes the accumulation of oncogenic proteins in a manner that precedes transcriptional activation. This function is mediated by succinate-triggered upregulation of ubiquitin-conjugating enzyme E2M (UBC12) phosphorylation, which impairs its E2 function in cullins neddylation. Notably, decreasing succinate by fludarabine can restore the sensitivity of anti-cancer drugs in SDH-deficient AML. Together, we uncover the function of succinate in driving drug resistance by regulating p-UBC12/cullin activity, and indicate reshaping succinate metabolism as a promising treatment for SDH-deficient AML.

Date: 2024
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DOI: 10.1038/s41467-024-53398-9

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