The mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) catalyzes one of the rate-limiting steps in de novo pyrimidine biosynthesis, a pathway that provides essential metabolic precursors for nucleic acids, glycoproteins, and phospholipids. DHODH inhibitors (DHODHi) are clinically used for autoimmune diseases and are emerging as a novel class of anticancer agents, especially in acute myeloid leukemia (AML) where pyrimidine starvation was recently shown to reverse the characteristic differentiation block in AML cells. Herein, we show that DHODH blockade rapidly shuts down protein translation in leukemic stem cells (LSCs) and has potent and selective activity against multiple AML subtypes. Moreover, we find that ablation of CDK5, a gene that is recurrently deleted in AML and related disorders, increases the sensitivity of AML cells to DHODHi. Our studies provide important molecular insights and identify a potential biomarker for an emerging strategy to target AML.

中文翻译：

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抑制嘧啶生物合成靶向急性髓细胞白血病中的蛋白质翻译

线粒体酶二氢乳清酸脱氢酶 (DHODH)从头催化限速步骤之一嘧啶生物合成，一种为核酸、糖蛋白和磷脂提供必需代谢前体的途径。DHODH 抑制剂 (DHODHi) 在临床上用于自身免疫性疾病，并且正在成为一类新型抗癌药物，特别是在急性髓性白血病 (AML) 中，最近显示嘧啶饥饿可逆转 AML 细胞中的特征性分化阻滞。在这里，我们表明 DHODH 阻断迅速关闭了白血病干细胞 (LSC) 中的蛋白质翻译，并对多种 AML 亚型具有有效和选择性的活性。此外，我们发现 CDK5（一种在 AML 和相关疾病中反复缺失的基因）的消融会增加 AML 细胞对 DHODHi 的敏感性。