MDS-Associated Spliceosome Mutations Regulate Host Defense

摘要 骨髓增生异常综合征（MDS）是一种以骨髓细胞为特征的造血干细胞疾病 分化缺陷和发育不良的血细胞产生。大多数 MDS 患者死于相关疾病 原因，其中感染或感染并发症是最常见的原因。虽然众所周知，骨髓 MDS 患者的细胞表现出功能缺陷，但这些缺陷的程度和原因仍不清楚，并且 对宿主防御的相应影响的研究有限。随着下一代的出现 测序技术，分析患者样本中的体细胞获得性突变已成为一种常态 MDS 患者临床实践的一部分。有趣的是，MDS 中最常见的突变类型 患者的剪接体的各个成分发生突变。我们已确定这些 MDS- 相关的剪接体基因突变导致先天免疫信号通路的改变 损害剪接体突变 MDS 小鼠模型中的骨髓细胞功能。这导致了 宿主防御的重大缺陷。基于这些初步研究，我们假设 MDS 存在剪接体突变的患者由于免疫功能障碍而面临更高的感染风险 他们的骨髓细胞。为了检验这个假设，我们将研究剪接体突变对宿主的影响 防御使用：（1）小鼠和人类中性粒细胞的离体研究，（2）小鼠和人类的离体研究 人类巨噬细胞，以及（3）表达突变剪接体基因的小鼠体内研究和分析 MDS 患者的临床数据。这些研究将确定宿主防御的机制 MDS 患者剪接体突变的缺陷，并将提供有关患者风险的重要临床数据 分层。

ABSTRACT Myelodysplastic Syndrome (MDS) is a hematopoietic stem cell disorder characterized by myeloid cell differentiation defects and dysplastic blood cell production. The majority of MDS patients die of disease related causes, with infection or infectious complications being the most common cause. While it is known that myeloid cells exhibit functional defects in MDS patients, the extent and cause of these defects remain unclear and the corresponding effects on host defense have received limited study. With the advent of next-generation sequencing technology, analysis of somatically-acquired mutations in patient samples has become a normal part of clinical practice in MDS patients. Interestingly, the most common class of mutations found in MDS patients are mutations in various components of the spliceosome. We have determined that these MDS- associated spliceosome gene mutations lead to alterations in innate immune signaling pathways and compromise the function of myeloid cells in mouse models of spliceosome-mutated MDS. This leads to a significant defect in host defense. Based on these preliminary studies, we have hypothesized that MDS patients with spliceosome mutations are at an increased risk of infection because of immune dysfunction in their myeloid cells. To test this hypothesis, we will investigate the effects of spliceosome mutations on host defense using: (1) ex vivo studies with mouse and human neutrophils, (2) ex vivo studies with mouse and human macrophages, and (3) in vivo studies in mice expressing mutant spliceosome genes and in an analysis of clinical data from patients with MDS. These studies will determine the mechanisms underlying host defense defects in MDS patients with spliceosome mutations and will provide important clinical data about patient risk stratification.