有缺陷的核糖体组装会损害急性髓样白血病的鼠模型中白血病的进展
Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia
影响因子:6.90000
分区:生物学1区 Top / 细胞生物学2区
发表日期:2024 Nov 26
作者:
Daniel Sjövall, Sudip Ghosh, Narcis Fernandez-Fuentes, Talia Velasco-Hernandez, Anna Hogmalm, Pablo Menendez, Jenny Hansson, Carolina Guibentif, Pekka Jaako
摘要
尽管对疾病机制有深入的了解，但目前的治疗方案仍无法治愈大多数急性髓性白血病（AML）的患者。在本研究中，我们解决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鼠模型来证明混合细胞性白血病重新培养AML中的未成熟白血病细胞的特征是相对较高的核糖体生物发生和蛋白质合成速率。使用具有可诱导的核糖体亚基连接的模型，我们表明有缺陷的核糖体组装扩展了使用AML的小鼠中的存活率。单细胞RNA测序和蛋白质组学分析表明，白血病细胞适应有缺陷的核糖体组装与核糖体生物发生的增加和转录因子景观的放松管制有关。最后，我们证明有缺陷的核糖体组装显示p53缺陷型AML中的抗肺血症功效。我们的研究揭示了高蛋白质合成率对白血病进展的关键要求，并将核糖体组装作为AML的治疗靶标。
Abstract
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.