Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Division of Hematology-Oncology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
Nat Commun. 2024 Nov 13;15(1):9820. doi: 10.1038/s41467-024-53398-9.
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.
耐药性是急性髓细胞白血病（AML）患者预后不良的关键因素，但其中的潜在机制仍知之甚少。鉴于骨髓的独特微环境，我们推测 AML 的耐药性可能依赖于不同的代谢过程。在这里，我们确定琥珀酸脱氢酶（SDH）缺陷和过度累积的琥珀酸是 AML 的典型特征，其在导致 AML 细胞对各种抗癌疗法的耐药性方面具有显著功能。在机制上，琥珀酸通过在转录激活之前促进致癌蛋白的积累来发挥作用。该功能由琥珀酸触发的泛素结合酶 E2M（UBC12）磷酸化上调介导，这会损害其在连接酶 neddylation 中的 E2 功能。值得注意的是，用氟达拉滨降低琥珀酸可以恢复 SDH 缺陷型 AML 中抗癌药物的敏感性。总之，我们揭示了琥珀酸通过调节 p-UBC12/连接酶活性来驱动耐药性的功能，并表明重塑琥珀酸代谢是治疗 SDH 缺陷型 AML 的一种有前途的方法。
