VEXAS anemia is a mosaic erythroblastopenia
Year: 2025
Type: article
Abstract: ABSTRACT: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently discovered autoinflammatory disorder linked to somatic mutations in the UBA1 gene, resulting in a profound cytoplasm-restricted defect in ubiquitylation. The disease is characterized by a macrocytic anemia that remains poorly understood. To investigate the erythroid lineage in VEXAS syndrome, we conducted a comprehensive study combining in vivo assessments of patients' mature red cells and marrow erythroblasts, alongside in vitro base-editing models of erythropoiesis. Here, we show that mature red cells do not exhibit ubiquitylation defects, and patient-derived bone marrow erythroblasts lack UBA1 mutations beyond the basophilic stage of erythroid differentiation. In vitro base editing of UBA1 variants in CD34+ primary cells resulted in high mortality during early erythroid differentiation but not during monocytic differentiation. Edited erythroid precursors displayed TP53 overexpression linked to defective ubiquitylation and anomalies in ribosome biogenesis, reminiscent of Diamond-Blackfan anemia. We propose that VEXAS syndrome-associated anemia should be considered as a mosaic erythroblastopenia, in which the severity of anemia is influenced by the quality and quantity of the UBA1-wild-type compartment. Our findings offer new insights into the physiopathology of VEXAS syndrome and may suggest new potential therapeutic options.
Source: Blood
Authors: François Rodrigues, Giulia Hardouin, Sara El Hoss, Aya Ghoul, Emilie-Fleur Gautier, Michaël Dussiot, Maria A. Lizarralde-Iragorri, Annalisa Santini, Sandy Peltier, Pascal Amireault, Vanessa Soldan, Annarita Miccio, Mounia Debili, Vincent Jachiet, Thiago Trovati Maciel, Julien Rossignol, Eric Allemand, Arsène Mekinian, Sophie Georgin-Lavialle, Mohammad Salma, Eric Soler, Pierre-Emmanuel Gleizes, Marie-Françoise O’Donohue, Olivier Kosmider, Manuel S. Rodriguez, Olivier Hermine, Jérome Hadjadj, Rim Bourguiba, Mael Heiblig, Chloé Mc Avoy, Valentin Lacombe, Samuel Ardois, Thibault Comont, Estibaliz Lazaro, Francois Lifermann, Guillaume Le, Herve Lobbes, Vincent Grobost, Roderau Outh, Yvan Jamilloux, Alexis Mathian, Jonathan Broner, Thomas Moulinet, Mikael Ebbo, Achille Aouba, François Chasset, Laurent Arnaud, Pierre Sujobert, Pierre Hirsch, Noémie Abisror, Pierre Fenaux, Olivier Kosmider, Vincent Jachiet, Olivier Fain, Benjamin Terrier, Sophie Georgin-Lavialle, Arsène Mekinian, Lin Pierre Zhao, Maxime Samson, Antoine Neel, Holy Bezanahary, Julien Rossignol, Shanti Ame, Alexandra Audemard-Verger, Ygal Benhamou, Jean David Bouaziz
Institutions: Inserm, Université Paris Cité, Institut des Maladies Génétiques Imagine, Centre National de la Recherche Scientifique, Institut Cochin, Biologie intégrée du globule rouge et de l'Erythropoïèse, Université Toulouse III - Paul Sabatier, Université de Toulouse, Centre de Biologie Intégrative de Toulouse, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Centre de Référence des Maladies Autoinflammatoires et des Amyloses, Hôpital Saint-Antoine, Hôpital Tenon, Université de Montpellier, Institut de Génétique Moléculaire de Montpellier, Hôpital Cochin, Laboratoire de Chimie de Coordination, Hôpital Necker-Enfants Malades
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funder: Agence Nationale de la Recherche
OpenAlex ID: W4414380519