U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) forms a heterodimeric complex with U2AF2 that is primarily responsible for 3ʹ splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). The U2AF heterodimer also has a noncanonical function as a translational regulator. Here, we report that the U2AF1-S34F mutation results in specific misregulation of the translation initiation and ribosome biogenesis machinery. The net result is an increase in mRNA translation at the single-cell level. Among the translationally up-regulated targets of U2AF1-S34F is Nucleophosmin 1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of the U2AF1-S34F mutant cells and causes ribosomal RNA (rRNA) processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation that recapitulates translational misregulation in myeloid disease.

U2小核RNA辅助因子1（U2AF1）与U2AF2形成异二聚体复合物，主要负责3′剪接位点的选择。U2AF1突变已在大多数癌症中发现，但普遍存在于骨髓增生异常综合症（MDS）和急性髓性白血病（AML）中，最常见的突变是将丝氨酸34误替换为苯丙氨酸（S34F）。U2AF异二聚体还具有非经典功能，如翻译调节子。在这里，我们报告U2AF1-S34F突变导致翻译起始和核糖体生物发生机制的特定失调。最终结果是单细胞水平的mRNA翻译增加。在U2AF1-S34F的翻译上调靶标中有Nucleophosmin 1（NPM1），它是髓系恶性肿瘤的主要驱动力。NPM1的消耗会削弱U2AF1-S34F突变细胞的生存能力，并导致核糖体RNA（rRNA）加工缺陷，从而表明U2AF1，NPM1和核糖体生物发生意想不到的合成相互作用。我们的结果为U2AF1突变建立了独特的分子表型，概括了髓样疾病中的翻译失调。