严格控制造血干细胞的决策对于终生健康的血液生产至关重要，也是造血系统疾病的根源。急性髓系白血病（AML）尤其是一种毁灭性的造血系统恶性肿瘤，它是由疾病起始原始细胞的克隆进化引起的，随着时间的推移，这些原始细胞会发生复杂的遗传变化，并最终产生白血病干细胞（LSC）。了解这些驱动细胞在整个发育过程中的分子基础将有助于拦截白血病、有效治疗白血病前期病症以及制定针对明确的 AML 疾病的策略。到目前为止，许多癌前骨髓疾病和与年龄相关的改变被证明是深入了解 LSC 启动的指导性模型。在这里，我们在转录后控制水平上探索这种骨髓失调，其中 RNA 结合蛋白 (RBP) 作为核心效应器。通过调节无数 RNA 代谢过程的相互作用，RBP 协调转录命运以控制健康和疾病中的基因表达。我们描述了人们对 RBP 及其转录后网络在维持健康造血作用中的作用的日益认识，以及它们在克隆性骨髓疾病和 AML 发病机制中的失调，特别强调了人类干细胞中描述的发现。最后，我们讨论了强调 RBP 和转录后控制作为 AML 精准治疗的可行目标的关键突破。© 2024 作者。约翰·威利 (John Wiley) 出版的 HemaSphere

Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post-transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post-transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post-transcriptional control as actionable targets for precision therapy of AML.© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.