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

IF 3.784 3区化学 Q1 Chemistry ACS Combinatorial Science Pub Date : 2024-11-13 DOI:10.1038/s41467-024-53398-9

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

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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.

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琥珀酸脱氢酶缺乏导致的琥珀酸积累通过泛素-瓜林调控诱导急性髓性白血病的耐药性

耐药性是急性髓性白血病（AML）患者预后不良的重要原因，但其潜在机制仍不甚明了。鉴于骨髓独特的微环境，我们推断急性髓细胞白血病的耐药性可能依赖于不同的代谢过程。在这里，我们发现琥珀酸脱氢酶（SDH）缺乏和琥珀酸过度累积是急性髓细胞性白血病的典型特征，它们在导致急性髓细胞性白血病细胞对各种抗癌疗法产生耐药性方面具有显著作用。从机理上讲，琥珀酸会在转录激活之前促进致癌蛋白质的积累。这种功能是由琥珀酸引发的泛素结合酶 E2M（UBC12）磷酸化上调介导的，这种磷酸化会损害其在瓜林内酰化过程中的 E2 功能。值得注意的是，通过氟达拉滨减少琥珀酸可恢复SDH缺陷急性髓细胞白血病患者对抗癌药物的敏感性。综上所述，我们揭示了琥珀酸盐通过调节p-UBC12/cullin活性驱动耐药性的功能，并指出重塑琥珀酸盐代谢是治疗SDH缺陷型急性髓细胞性白血病的有效方法。

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ACS Combinatorial Science CHEMISTRY, APPLIED-CHEMISTRY, MEDICINAL

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审稿时长

1 months

期刊介绍： The Journal of Combinatorial Chemistry has been relaunched as ACS Combinatorial Science under the leadership of new Editor-in-Chief M.G. Finn of The Scripps Research Institute. The journal features an expanded scope and will build upon the legacy of the Journal of Combinatorial Chemistry, a highly cited leader in the field.