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

Author

Listed:
  • 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
    Ministry of Education
    Zhejiang University)

  • Qiaojun He

    (Zhejiang University
    Ministry of Education
    Zhejiang University)

  • Bo Yang

    (Zhejiang University
    Ministry of Education
    Zhejiang University)

  • Meidan Ying

    (Zhejiang University
    Zhejiang University School of Medicine, National Clinical Research Center for Child Health
    Ministry of Education
    Zhejiang University)

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.

Suggested Citation

  • 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 & Meidan Ying, 2024. "Succinate dehydrogenase deficiency-driven succinate accumulation induces drug resistance in acute myeloid leukemia via ubiquitin-cullin regulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53398-9
    DOI: 10.1038/s41467-024-53398-9
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