尽管对疾病机制有了深入的了解，但目前的治疗方案仍无法治愈大多数急性髓系白血病 (AML) 患者。在本研究中，我们探讨了核糖体组装在白血病细胞功能中的作用。我们应用患者数据集和小鼠模型来证明混合谱系白血病重排 AML 中未成熟的白血病细胞具有相对较高的核糖体生物发生和蛋白质合成率。使用核糖体亚基连接诱导调节模型，我们发现有缺陷的核糖体组装可延长 AML 小鼠的生存期。单细胞 RNA 测序和蛋白质组学分析表明，白血病细胞对核糖体组装缺陷的适应与核糖体生物发生的增加和转录因子景观的失调有关。最后，我们证明有缺陷的核糖体组装在 p53 缺陷的 AML 中显示出抗白血病功效。我们的研究揭示了白血病进展对高蛋白质合成率的关键要求，并强调核糖体组装作为 AML 的治疗靶点。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Despite an advanced understanding of disease mechanisms, the current therapeutic regimen fails to cure most patients with acute myeloid leukemia (AML). In the present study, we address the role of ribosome assembly in leukemia cell function. We apply patient datasets and murine models to demonstrate that immature leukemia cells in mixed-lineage leukemia-rearranged AML are characterized by relatively high ribosome biogenesis and protein synthesis rates. Using a model with inducible regulation of ribosomal subunit joining, we show that defective ribosome assembly extends survival in mice with AML. Single-cell RNA sequencing and proteomic analyses reveal that leukemia cell adaptation to defective ribosome assembly is associated with an increase in ribosome biogenesis and deregulation of the transcription factor landscape. Finally, we demonstrate that defective ribosome assembly shows antileukemia efficacy in p53-deficient AML. Our study unveils the critical requirement of a high protein synthesis rate for leukemia progression and highlights ribosome assembly as a therapeutic target in AML.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.