Mechanisms of hematopoietic clonal dominance in VEXAS syndrome

Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms driving clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic characterization of hematopoiesis and single-cell transcriptomics in a cohort of 9 male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem/progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs. Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytologic alterations, and senescence signatures of patients’ cells, as well as disease hematologic and inflammatory hallmarks. Competitive transplants of human UBA1-mutant and wild-type HSPCs showed that while mutant cells are more resilient to the inflammatory milieu, likely through the acquisition of the senescence-like state, wild-type ones are progressively exhausted and overwhelmed by VEXAS clones, overall impairing functional hematopoiesis and leading to bone marrow failure. Our study unveils the mechanism of clonal dominance, provides models for preclinical investigation of therapeutic strategies, and might have implications for clinical management of VEXAS syndrome.