Mechanisms of hematopoietic clonal dominance in VEXAS syndrome
Raffaella Molteni, Martina Fiumara, Corrado Campochiaro, Roberta Alfieri, Guido Pacini, Eugenia Licari, Alessandro Tomelleri, Elisa Diral, Angelica Varesi, Alessandra Weber, Pamela Quaranta, Luisa Albano, Chiara Gaddoni, Luca Basso‐Ricci, Davide Stefanoni, Laura Alessandrini, S. Degl’Innocenti, Francesca Sanvito, Gregorio Maria Bergonzi, Andrea Annoni, Maddalena Panigada, Eleonora Cantoni, Daniele Canarutto, Stephanie Z. Xie, Angelo D’Alessandro, Raffaella Di Micco, Alessandro Aiuti, Fabio Ciceri, Giacomo De Luca, Lorenzo Dagna, Marco Matucci‐Cerinic, Ivan Merelli, Simone Cenci, Serena Scala, Giulio Cavalli, Luigi Naldini, Samuele Ferrari
Abstract
Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common nonmalignant 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. In the present study, we performed immunophenotype characterization of hematopoiesis and single-cell transcriptomics in a cohort of nine male patients with VEXAS syndrome, revealing pervasive inflammation across all lineages. Hematopoietic stem and 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, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks. Competitive transplantations of human UBA1-mutant and wild-type HSPCs showed that, although mutant cells are more resilient to the inflammatory milieu, probably 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 and provides models for preclinical studies and preliminary insights that could inform therapeutic strategies.