Fig. 6: Proinflammatory poisoning of healthy hematopoiesis drives clonal dominance in VEXAS syndrome.

a, Schematics of the in vivo competitive transplantation experiment mixing UBA1^mut and UBA1^wt HSPCs at different ratios. b,c, Number of human cells from the different hematopoietic compartments in the BM (b) and PB (c) of mice transplanted as shown in a (n = 5 per group). The median is shown with the IQR. d,e, Percentage of human hematopoietic cells within total live cells in the BM (d) and PB (e) of mice from b (n = 5 mice per group). The values are the mean ± s.e.m. f, Number of human and mouse cells in the BM of mice from b (n = 5 mice per group). The median is shown with the IQR. g, Ratio between the number of myeloid and lymphoid cells (n = 5 mice per group). The median is shown with the IQR. h,i, Number of lymphoid (h) and myeloid (i) cell subpopulations in mice from b (n = 5 mice per group). The median is shown with the IQR. j, Number of CD34⁺ HSPCs in mice from b (n = 5 mice per group). The median is shown with the IQR. k, Percentage of HSPC subpopulations in the BM of mice from b (n = 5 mice per group). The right panel zooms in the most primitive HSPC compartment. The values are the mean ± s.e.m. l–n, Number of UBA1^mut and UBA1^wt HSPCs (l), myeloid cells (m) and B cells (n) (n = 5 mice per group). The median is shown with the IQR. o, Percentage of UBA1^mut cells within each hematopoietic subpopulation in the mixed groups (n = 5 mice per group). Dotted squares indicate the percentage of infused UBA1^mut HSPCs. The median is shown with the IQR. p, Concentrations of human cytokines in the BM of UBA1^mut and UBA1^wt mice 4 weeks after transplantation (n = 3, 4). q, UMAP plot of human CD45⁺ cells, enriched in the CD34⁺ HSPC fraction, from the BM of mice transplanted with 50% UBA1^wt or UBA1^mut HSPCs. Clusters and associated cell types are indicated by name and color. r, Heatmap as in Fig. 4c showing NESs for the GSEA performed within clusters in q comparing UBA1^wt female cells from VEXAS mice versus UBA1^wt female cells from wild-type mice. Wilcoxon’s rank-sum test with the Holm–Bonferroni correction was used and, for all other panels, the Kruskal–Wallis test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Panel a created with BioRender.com.