Elbadry Mahmoud I, Mabed Mohamed
Department of Internal Medicine, Division of Haematology, Faculty of Medicine, Sohag University, Sohag, Egypt.
Hematology and Bone Marrow Transplantation Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Eur J Haematol. 2025 Sep;115(3):204-217. doi: 10.1111/ejh.14441. Epub 2025 May 29.
Bone marrow (BM) vacuolization is a key morphological feature observed in VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. However, vacuolization alone is not specific to VEXAS, as it can also be seen in conditions such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), metabolic disorders, and toxic exposures. VEXAS syndrome, a postzygotic mutation-driven autoinflammatory disease caused by somatic mutations in the UBA1 gene, leads to chronic immune activation, clonal expansion of hematopoietic cells, and systemic inflammation. UBA1 mutations result in protein misfolding, contributing to both hematologic and inflammatory abnormalities. In VEXAS syndrome, specific features of vacuolated progenitor cells suggest the diagnosis. These include a high number of vacuolated cells, increased vacuoles per cell, a predominance of vacuoles in early progenitors rather than later stages, and vacuolization in both myeloid and erythroid progenitors, with myeloid progenitors most affected. However, the absence or low frequency of vacuolated cells should not rule out the possibility of VEXAS, and UBA1 gene sequencing should still be considered, especially in patients with unexplained systemic inflammation, MDS, or associated with other hematologic disorders. These mutations may alter the BM microenvironment, promoting the survival and expansion of mutant clones, which drive disease progression. While there is no standard treatment for VEXAS, the condition provides a unique model for understanding how inflammation in the BM microenvironment contributes to clonal selection and hematologic malignancy development. Research into the genetic and molecular mechanisms behind BM vacuolization in VEXAS has improved the diagnostic approaches and enhanced our understanding of its impact on hematopoiesis. Ongoing studies into the interplay between vacuolization, clonal hematopoiesis, and immune dysregulation will be a key to developing effective therapies for this complex syndrome. We herein offer a comprehensive diagnostic approach to BM vacuolization linked to VEXAS syndrome, distinguishing it from vacuoles observed in other conditions. The analysis delves into the clinical and hematologic features, molecular pathways, and rapidly evolving diagnostic methods for VEXAS syndrome, emphasizing its impact on hematopoiesis from a hematologic perspective.
骨髓空泡化是VEXAS（空泡、E1酶、X连锁、自身炎症性、体细胞）综合征中观察到的关键形态学特征。然而，单纯的空泡化并非VEXAS所特有，因为在骨髓增生异常综合征（MDS）、急性髓系白血病（AML）、代谢紊乱和有毒物质暴露等情况下也可见到。VEXAS综合征是一种由UBA1基因体细胞突变驱动的合子后突变性自身炎症性疾病，导致慢性免疫激活、造血细胞克隆性扩增和全身炎症。UBA1突变导致蛋白质错误折叠，导致血液学和炎症异常。在VEXAS综合征中，空泡化祖细胞的特定特征提示诊断。这些特征包括大量空泡化细胞、每个细胞的空泡增加、早期祖细胞而非后期阶段空泡占优势，以及髓系和红系祖细胞均有空泡化，其中髓系祖细胞受影响最大。然而，空泡化细胞的缺失或低频率出现不应排除VEXAS的可能性，仍应考虑进行UBA1基因测序，特别是对于原因不明的全身炎症、MDS或与其他血液系统疾病相关的患者。这些突变可能改变骨髓微环境，促进突变克隆的存活和扩增，从而推动疾病进展。虽然VEXAS没有标准治疗方法，但这种疾病为理解骨髓微环境中的炎症如何促成克隆选择和血液系统恶性肿瘤发展提供了一个独特模型。对VEXAS中骨髓空泡化背后的遗传和分子机制的研究改进了诊断方法，并增强了我们对其对造血影响的理解。对空泡化、克隆性造血和免疫失调之间相互作用的持续研究将是开发针对这种复杂综合征的有效疗法的关键。我们在此提供一种与VEXAS综合征相关的骨髓空泡化的综合诊断方法，将其与其他情况下观察到的空泡区分开来。该分析深入探讨了VEXAS综合征的临床和血液学特征、分子途径以及快速发展的诊断方法，从血液学角度强调其对造血的影响。
