骨髓增生异常综合征（MDS）是一种造血干细胞障碍，可能发展为急性髓系白血病。致命感染是MDS患者最常见的死亡原因之一，很可能是由于这些患者的髓系细胞细胞减少和功能障碍导致的。编码剪接体组分的基因突变被认为是MDS患者中最常见的体细胞获得性突变类别。为了确定MDS患者宿主防御缺陷的分子基础，我们使用一种转基因小鼠模型，该模型表达了与MDS相关的剪接体基因突变U2AF1-S34F。我们发现，U2AF1-S34F在这些小鼠中引起了严重的宿主防御缺陷，很可能是通过诱导重要的中性粒细胞趋化缺陷来实现的。对人中性粒细胞的研究表明，U2AF1-S34F这种影响很可能也存在于MDS患者中。RNA-seq分析表明，这种剪接体突变会影响多个介导细胞迁移的基因的表达，因此很可能是导致中性粒细胞功能障碍的驱动因素。© 2023. 作者。

Myelodysplastic neoplasm (MDS) is a hematopoietic stem cell disorder that may evolve into acute myeloid leukemia. Fatal infection is among the most common cause of death in MDS patients, likely due to myeloid cell cytopenia and dysfunction in these patients. Mutations in genes that encode components of the spliceosome represent the most common class of somatically acquired mutations in MDS patients. To determine the molecular underpinnings of the host defense defects in MDS patients, we investigated the MDS-associated spliceosome mutation U2AF1-S34F using a transgenic mouse model that expresses this mutant gene. We found that U2AF1-S34F causes a profound host defense defect in these mice, likely by inducing a significant neutrophil chemotaxis defect. Studies in human neutrophils suggest that this effect of U2AF1-S34F likely extends to MDS patients as well. RNA-seq analysis suggests that the expression of multiple genes that mediate cell migration are affected by this spliceosome mutation and therefore are likely drivers of this neutrophil dysfunction.© 2023. The Author(s).