Fig. 5: Patients with VEXAS syndrome are hallmarked by pan-lineage activation of inflammatory programs, downregulation of cell-cycle-related genes and ineffective erythropoiesis.

a, UMAP plot of hematopoietic cells from the BM of patients with VEXAS syndrome from the San Raffaele (PT1, PT2, PT3, PT5, PT8 and PT9) and Wu et al.⁴⁴ cohorts and age-matched controls. Clusters and associated cell types are indicated by name and color. b, Heatmap as in Fig. 4c showing the NESs for the GSEA performed within the CD34⁻ clusters from a. Wilcoxon’s rank-sum test with the Benjamini–Hochberg correction was used. c, Volcano plots showing fold-changes of upregulated (red) and downregulated (green) genes comparing patients with VEXAS syndrome and controls within the ‘late erythroid cell’ cluster. Nonsignificant genes are shown in gray. Wilcoxon’s rank-sum test with the Benjamini–Hochberg correction was used. d, UMAP plot of human CD34⁺ cells from the BM of patients with VEXAS syndrome (San Raffaele and Wu et al.⁴⁴ cohorts) and age-matched controls^44,72. Clusters and associated cell types are indicated by name and color. ‘VEXAS-enr’ labels cluster with predominance of cells from patients with VEXAS syndrome. e,f, Heatmap as in Fig. 4c showing NESs for the GSEA performed within the CD34⁺ clusters from d in all patients (e) or in patients with the threonine mutation (f). Wilcoxon’s rank-sum test with the Benjamini–Hochberg correction was used. g,h, UCell scores based on the ‘VEXAS xenograft signature’ within CD34⁺ (g) and CD34⁻ (h) clusters from patients with VEXAS syndrome and controls. The signature was built considering the top-50 upregulated genes in UBA1^mut monocytes compared with the UBA1^wt counterpart. Wilcoxon’s rank-sum test with the Holm–Bonferroni correction was used. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. NS, nonsignificant; ery, erythroid; hemato, hematopoietic; hom, homeostasis.