转录后机制是祖细胞身份的基本保障，并且在癌症中经常失调。在这里，我们通过正常和恶性造血祖细胞的全基因组 CRISPR 筛选，确定了 P 体的调节因子是急性髓系白血病 (AML) 的关键漏洞。我们发现白血病细胞中 P 体数量异常升高，并表明 P 体组装对于 AML 的启动和维持至关重要。值得注意的是，P-体损失对稳态造血影响不大，但影响再生造血。从人类 AML 细胞中纯化的 P 体的分子表征揭示了它们在从翻译机制中隔离编码有效肿瘤抑制因子的信使 RNA 中的关键作用。 P-体溶解促进了这些 mRNA 的翻译，进而重新连接了白血病细胞中的基因表达和染色质结构。总的来说，我们的研究结果强调了 P 体中 RNA 隔离在组织稳态和肿瘤发生过程中的对比和独特作用。这些见解为了解髓性白血病和未来治疗干预措施开辟了潜在途径。© 2024。作者，获得 Springer Nature Limited 的独家许可。

Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.