Molteni Raffaella, Fiumara Martina, Campochiaro Corrado, Alfieri Roberta, Pacini Guido, Licari Eugenia, Tomelleri Alessandro, Diral Elisa, Varesi Angelica, Weber Alessandra, Quaranta Pamela, Albano Luisa, Gaddoni Chiara, Basso-Ricci Luca, Stefanoni Davide, Alessandrini Laura, Degl'Innocenti Sara, Sanvito Francesca, Bergonzi Gregorio Maria, Annoni Andrea, Panigada Maddalena, Cantoni Eleonora, Canarutto Daniele, Xie Stephanie Z, D'Alessandro Angelo, Di Micco Raffaella, Aiuti Alessandro, Ciceri Fabio, De Luca Giacomo, Dagna Lorenzo, Matucci-Cerinic Marco, Merelli Ivan, Cenci Simone, Scala Serena, Cavalli Giulio, Naldini Luigi, Ferrari Samuele
Vita-Salute San Raffaele University, Milan, Italy.
Inflammation Fibrosis and Ageing Initiative (INFLAGE), Division of Genetics and Cell Biology, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Nat Med. 2025 Apr 7. doi: 10.1038/s41591-025-03623-9.
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.
克隆优势是衰老过程中造血作用的特征，会增加患血癌和常见非恶性疾病的易感性。VEXAS综合征是一种最近发现的成年发病的自身炎症性疾病，死亡率高，由在UBA1基因中携带体细胞突变的显性造血克隆引起。然而，驱动克隆优势的致病机制尚不清楚。此外，缺乏疾病模型阻碍了疾病修饰疗法的发展。在本研究中，我们对一组9名患有VEXAS综合征的男性患者进行了造血免疫表型特征分析和单细胞转录组学研究，发现所有谱系中均存在普遍炎症。患者的造血干细胞和祖细胞（HSPCs）倾向于髓系造血，并获得类似衰老的程序。通过碱基编辑在健康HSPCs中插入致病突变产生的VEXAS综合征人源化模型，概括了患者细胞的蛋白质稳态缺陷、细胞学改变和衰老特征，以及血液学和炎症性疾病特征。人UBA1突变型和野生型HSPCs的竞争性移植表明，尽管突变细胞可能通过获得类似衰老的状态而对炎症环境更具弹性，但野生型细胞会逐渐耗尽，并被VEXAS克隆压倒，总体上损害功能性造血并导致骨髓衰竭。我们的研究揭示了克隆优势的机制，并为临床前研究提供了模型以及可为治疗策略提供信息的初步见解。
