In a phenotypical screen of 56 acute myeloid leukemia (AML) patient samples and using a library of 10,000 compounds, we identified a hit with increased sensitivity toward SF3B1 -mutated and adverse risk AMLs. Through structure-activity relationship studies, this hit was optimized into a potent, specific, and nongenotoxic molecule called UM4118. We demonstrated that UM4118 acts as a copper ionophore that initiates a mitochondrial-based noncanonical form of cell death known as cuproptosis. CRISPR-Cas9 loss-of-function screen further revealed that iron-sulfur cluster (ISC) deficiency enhances copper-mediated cell death. Specifically, we found that loss of the mitochondrial ISC transporter ABCB7 is synthetic lethal to UM4118. ABCB7 is misspliced and down-regulated in SF3B1 -mutated leukemia, creating a vulnerability to copper ionophores. Accordingly, ABCB7 overexpression partially rescued SF3B1 -mutated cells to copper overload. Together, our work provides mechanistic insights that link ISC deficiency to cuproptosis, as exemplified by the high sensitivity of SF3B1 -mutated AMLs. We thus propose SF3B1 mutations as a biomarker for future copper ionophore–based therapies.

中文翻译：

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SF3B1突变导致人类急性髓系白血病对铜离子载体的遗传脆弱性

在对 56 名急性髓系白血病 (AML) 患者样本进行表型筛选并使用包含 10,000 种化合物的库中，我们发现了一种对SF3B1-突变和不良风险的 AML。通过结构-活性关系研究，这种命中被优化为一种有效的、特异性的、无基因毒性的分子，称为 UM4118。我们证明 UM4118 作为铜离子载体，启动一种基于线粒体的非典型细胞死亡形式，称为铜凋亡。 CRISPR-Cas9 功能丧失筛选进一步揭示铁硫簇 (ISC) 缺陷会增强铜介导的细胞死亡。具体来说，我们发现线粒体 ISC 转运蛋白的丢失ABCB7对 UM4118 具有合成致死性。ABCB7被错误拼接和下调SF3B1-突变的白血病，对铜离子载体造成脆弱性。因此，ABCB7 过度表达部分得到拯救SF3B1- 细胞发生铜超载突变。总之，我们的工作提供了将 ISC 缺陷与铜凋亡联系起来的机制见解，例如SF3B1-突变的 AML。因此我们建议SF3B1突变作为未来基于铜离子载体的疗法的生物标志物。