BloodSep 19, 2025

VEXAS anemia involves a mixed loss of red blood cell precursors

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 3, 2026

Abstract

VEXAS syndrome is associated with macrocytic anemia linked to mutations in the UBA1 gene.

Mature red cells from VEXAS patients do not show defects in ubiquitylation.
Bone marrow erythroblasts from patients lack UBA1 mutations beyond the basophilic stage of development.
In vitro editing of UBA1 variants in early erythroid precursors leads to high cell mortality.
Edited erythroid precursors exhibit overexpression of TP53, associated with ubiquitylation defects.
The findings suggest VEXAS-associated anemia could be viewed as a mosaic erythroblastopenia influenced by UBA1-WT levels.

Simplified

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation, but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.

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VEXAS anemia involves a mixed loss of red blood cell precursors

Abstract

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