Bone Marrow Vacuolization at the Crossroads of Specialties: Molecular Insights and Diagnostic Challenges

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.