syndrome was only observed in male patients.The somatic UBA1 p.Met41 mutations were observed in more than half of the circulating blood cells, including peripheral blood myeloid cells, but not in lymphocytes or fibroblasts.Consistent with UBA1's role as the initiating enzyme in the ubiquitination pathway, the cells of patients with VEXAS syndrome exhibited a profound cytoplasm-restricted defect in ubiquitylation. 2ortly after the original description, many other groups confirmed that UBA1 p.Met41 mutations were present in the peripheral blood of patients with inflammatory syndromes and also in some patients with bone marrow failure syndromes 3,4 (reviewed in Grayson et al 5 ).Many treatment strategies that target inflammation have shown benefit in isolated patients with VEXAS syndrome, but most patients are refractory to any treatment. 6,7e study by Rodrigues et al makes a great step forward in understanding the anemia in VEXAS syndrome.First, the authors showed that the red blood cells in patients with VEXAS syndrome had normal indices.They hypothesized and demonstrated that mature erythroid cells were derived from wild-type progenitor cells, although the UBA1 mutation was seen in the majority of myeloid cells.The authors concluded that the UBA1 mutant cells could not complete erythropoiesis.They then used base editing in male CD34 + cells, followed by in vitro differentiation into erythroid cells, to show that erythropoiesis was completely inhibited in mutant cells with massive apoptosis after the early erythroid stage.These results explained the clonal dominance of the UBA-mutated progenitors and the anemia in VEXAS syndrome.The results do not support the competing model in which inflammation suppresses erythropoiesis, thereby resolving some controversies in the field.The edited UBA1-mutated early erythroid precursors displayed TP53 overexpression that was linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia.Based on these observations, the authors hypothesized that proteosome inhibition could be a novel approach to treating at least the erythroid defects in VEXAS syndrome. 1This summary is nicely encapsulated in the virtual abstract that accompanies the study. 1 The experiments described in the study by Rodrigues et al are well controlled, and the results support their hypotheses strongly.More broadly, the approach of focusing on a specific aspect of the much more complicated VEXAS syndrome is an outstanding example of how a mechanistic study can open the door for a greater understanding of other aspects of VEXAS syndrome.
Blumenberg et al. (Thu,) studied this question.