美国贝勒医学院Bruno Di Stefano等研究人员合作发现，RNA在P小体中的隔离维持髓系白血病。这一研究成果于2024年8月21日在线发表在国际学术期刊《自然—细胞生物学》上。

研究人员通过对正常和恶性造血前体进行全基因组CRISPR筛选，识别了P小体调节因子作为急性髓系白血病（AML）中的关键脆弱点。研究人员发现白血病细胞中存在异常增多的P小体，并表明P小体的组装对AML的发生和维持至关重要。

值得注意的是，P小体的丧失对稳态造血的影响很小，但对再生造血产生了影响。对人类AML细胞中提纯的P小体进行分子特征分析揭示了它们在从转录机器中隔离编码强效肿瘤抑制因子mRNA方面的关键作用。P小体的解离促进了这些mRNA的翻译，从而重塑了白血病细胞中的基因表达和染色质结构。

总的来说，这些发现突出了RNA在P小体中隔离在组织稳态和癌发生过程中的相反和独特作用。这些见解为理解髓系白血病及未来的治疗干预提供了潜在的方向。

研究人员表示，转录后机制是保护前体细胞身份的基本机制，且在癌症中常常出现失调。

附：英文原文

Title: RNA sequestration in P-bodies sustains myeloid leukaemia

Author: Kodali, Srikanth, Proietti, Ludovica, Valcarcel, Gemma, Lpez-Rubio, Anna V., Pessina, Patrizia, Eder, Thomas, Shi, Junchao, Jen, Annie, Lupin-Garcia, Nria, Starner, Anne C., Bartels, Mason D., Cui, Yingzhi, Sands, Caroline M., Planas-Riverola, Ainoa, Martnez, Alba, Velasco-Hernandez, Talia, Toms-Daza, Laureano, Alber, Bernhard, Manhart, Gabriele, Mayer, Isabella Maria, Kollmann, Karoline, Fatica, Alessandro, Menendez, Pablo, Shishkova, Evgenia, Rau, Rachel E., Javierre, Biola M., Coon, Joshua, Chen, Qi, Van Nostrand, Eric L., Sardina, Jose L., Grebien, Florian, Di Stefano, Bruno

Issue&Volume: 2024-08-21

Abstract: 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.

DOI: 10.1038/s41556-024-01489-6

Source: https://www.nature.com/articles/s41556-024-01489-6