缺陷的核糖体装配抑制急性髓性白血病的白血病进展——基于小鼠模型的研究

Defective ribosome assembly impairs leukemia progression in a murine model of acute myeloid leukemia

Cell Reports

影响因子:6.9

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

DOI: 10.1016/j.celrep.2024.114864

摘要

尽管对疾病机制已有较深的理解，但目前的治疗方案仍无法治愈大多数急性髓性白血病（AML）患者。本研究关注核糖体装配在白血病细胞功能中的作用。我们利用患者数据和小鼠模型，证明在混合谱系白血病重排AML中，未成熟白血病细胞表现出较高的核糖体生物合成和蛋白质合成速率。通过可诱导调控核糖体亚基连接的模型，我们发现缺陷的核糖体装配能延长AML小鼠的生存期。单细胞RNA测序和蛋白质组分析显示，白血病细胞对缺陷核糖体装配的适应与核糖体生物合成的增加和转录因子景观的失调相关。最后，我们证实在p53缺失的AML中，缺陷的核糖体装配表现出抗白血病效果。我们的研究揭示了高蛋白质合成速率对白血病进展的关键需求，并将核糖体装配作为AML的潜在治疗靶点。

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.