Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
Nat Cell Biol. 2024 Oct;26(10):1745-1758. doi: 10.1038/s41556-024-01489-6. Epub 2024 Aug 21.
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.
转录后机制是祖细胞身份的基本保障，在癌症中经常失调。在这里，我们通过对正常和恶性造血祖细胞进行全基因组 CRISPR 筛选，确定 P 体作为急性髓系白血病 (AML) 的关键脆弱性。我们发现白血病细胞中 P 体的数量异常升高，并表明 P 体的组装对于 AML 的起始和维持至关重要。值得注意的是，P 体的缺失对同源造血几乎没有影响，但对再生造血有影响。从人 AML 细胞中纯化的 P 体的分子特征揭示了它们在将编码强效肿瘤抑制剂的信使 RNA 从翻译机制中隔离出来的关键作用。P 体的溶解促进了这些 mRNA 的翻译，进而重新布线了白血病细胞中的基因表达和染色质结构。总的来说，我们的发现强调了 RNA 隔离在组织同源性和肿瘤发生过程中 P 体的对比和独特作用。这些见解为理解髓性白血病和未来的治疗干预提供了潜在途径。
