Hematology Branch, National Heart, Lung, NIH, Blood Institute (NHLBI), Bethesda, MD.
Hematology Branch, National Heart, Lung, NIH, Blood Institute (NHLBI), Bethesda, MD.
Semin Hematol. 2022 Jul;59(3):156-166. doi: 10.1053/j.seminhematol.2022.07.003. Epub 2022 Aug 3.
Somatic mutations have been increasingly identified as etiologic for many hematologic and autoinflammatory disorders. VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome and Erdheim-Chester disease (ECD), a type of histiocytosis, can be classified as inflammatory myeloid diseases, characterized by systemic inflammation and multi-organ disease with predisposition to myeloid malignancies. VEXAS is a novel disease caused by UBA1 mutations that was first discovered using a genotype-driven approach (genotype was used to identify patients with undiagnosed inflammatory diseases). Since the initial description, many VEXAS cases have been reported and disease phenotype is expanding rapidly. In contrast, ECD was first characterized in the 1930s based on patients' phenotype, and only recently found to be caused by recurrent somatic mutations in the MAPK pathway (traditional phenotype-driven approach). The discovery of these mutations and development of target therapies have revolutionized the treatment of patients with histiocytosis, particularly ECD. Here we discuss the impact of causal and associated somatic mutations in VEXAS and ECD at both clinical and molecular levels.
体细胞突变已被越来越多地确定为许多血液学和自身炎症性疾病的病因。VEXAS（空泡、E1 酶、X 连锁、自身炎症、体细胞）综合征和 Erdheim-Chester 病（ECD）是一种组织细胞增多症，可以归类为炎症性髓系疾病，其特征是全身炎症和多器官疾病，易发生髓系恶性肿瘤。VEXAS 是一种由 UBA1 突变引起的新型疾病，最初是通过基因型驱动的方法（使用基因型来识别未确诊的炎症性疾病患者）发现的。自最初描述以来，已经报告了许多 VEXAS 病例，并且疾病表型正在迅速扩展。相比之下，ECD 最初是根据患者的表型在 20 世纪 30 年代进行描述的，直到最近才发现是由 MAPK 通路中的反复体细胞突变引起的（传统的表型驱动方法）。这些突变的发现和靶向治疗的发展彻底改变了组织细胞增多症患者的治疗方法，尤其是 ECD。在这里，我们将讨论 VEXAS 和 ECD 中因果和相关体细胞突变在临床和分子水平上的影响。
