VEXAS anemia is a mosaic erythroblastopenia

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, 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-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.

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Publication Details

Journal
Blood
Published
2025-09-19
DOI
https://doi.org/10.1182/blood.2025029081
Citations
2
Primary Topic
Otitis Media and Relapsing Polychondritis
Type
article
Field-Weighted Citation Impact
3.34

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article

VEXAS anemia is a mosaic erythroblastopenia

Marie-Françoise O’Donohue, Emilie‐Fleur Gautier, Sophie Georgin‐Lavialle, Annarita Miccio et al.
2 citations
Blood
Otitis Media and Relapsing Polychondritis
3.34
article

VEXAS anemia is a mosaic erythroblastopenia

Marie-Françoise O’Donohue, Emilie‐Fleur Gautier, Sophie Georgin‐Lavialle, Annarita Miccio, Olivier Kosmider, Giulia Hardouin, S. Peltier, Pascal Amireault, Thiago Trovati Maciel, Eric Allemand, François Rodrigues, Maria A. Lizarralde-Iragorri, Vanessa Soldan, Annalisa Santini, Pierre‐Emmanuel Gleizes, Olivier Hermine, Sara El Hoss, Mohammad Salma, Julien Rossignol, Éric Soler, Vincent Jachiet, Michaël Dussiot, A. Mékinian, Manuel S. Rodríguez, Mounia Debili, Aya Ghoul
article en
2 citations

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, 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-associated anemia should be considered as a mosaic erythroblastopenia, where the severity of anemia is influenced by the quality and quantity of the UBA1-WT compartment. Our findings offer new insights into the physiopathology of VEXAS and may suggest new potential therapeutic options.

BloodVol. 147(11)
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Université Toulouse III - Paul Sabatier (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Université de Montpellier (FR), Université Paris Cité (FR), Sorbonne Université (FR), Hôpital Cochin (FR), Assistance Publique – Hôpitaux de Paris (FR), Centre de Biologie du Développement (FR), Centre de Référence des Maladies Autoinflammatoires et des Amyloses (FR), Centre d'Études Spatiales de la Biosphère (FR), Hôpital Saint-Antoine (FR), Institut de Génétique Moléculaire de Montpellier (FR), Laboratoire de Chimie de Coordination (FR), Sadir Assistance (FR), Institut Cochin (FR), Cellular Research (United States) (US), Biologie intégrée du globule rouge et de l'Erythropoïèse (FR), International Union for Electricity applications (FR), Institut des Maladies Génétiques Imagine (FR), Hôpital Tenon (FR)
Agence Nationale de la Recherche
Openalex Percentile: Top 7%
Otitis Media and Relapsing Polychondritis
3.34
DOIOpen Access PDFOpenAlex
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