SF3B1是骨髓增殖性疾病（MDS）中最常发生突变的剪接因子（SF），这些疾病是克隆性造血障碍，具有白血病转化风险的差异性。虽然已广泛描述了致瘤性SF3B1突变，但“未突变”野型SF3B1在癌症中的作用仍未被完全解决。在这里，我们确定了一个保守的表观转录组学程序，用于调控SF3B1水平以抵制白血病生成。我们对人类和鼠类前白血病MDS细胞的分析揭示了SF3B1蛋白丰度的动态调节，它影响了MDS到白血病转化的体内过程。在机制上，ALKBH5受驱动的5'UTR m6A去甲基化微调SF3B1翻译，指导转录中央DNA修复和表观遗传调节因子的劈切过程。这影响基因组稳定性和白血病体内进展，支持一个综合人类分析，即SF3B1分子标记可能预测突变多样性和不良预后。这些发现突显了一个后转录基因表达中枢，揭示了意想不到的SF3B1依赖性癌症易感性。版权所有©2023作者。Elsevier Inc.保留所有权利。

SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDSs), which are clonal hematopoietic disorders with variable risk of leukemic transformation. Although tumorigenic SF3B1 mutations have been extensively characterized, the role of "non-mutated" wild-type SF3B1 in cancer remains largely unresolved. Here, we identify a conserved epitranscriptomic program that steers SF3B1 levels to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals dynamic regulation of SF3B1 protein abundance, which affects MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven 5' UTR m6A demethylation fine-tunes SF3B1 translation directing splicing of central DNA repair and epigenetic regulators during transformation. This impacts genome stability and leukemia progression in vivo, supporting an integrative analysis in humans that SF3B1 molecular signatures may predict mutational variability and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.