VEXAS anemia is a mosaic erythroblastopenia
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.
Article Details
Authors (61)
François Rodrigues
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Giulia Hardouin
4Laboratory of Chromatin and Gene Regulation During Development, Université Paris Cité, Imagine Institute, INSERM 1163, Paris, France
Sara El Hoss
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Aya Ghoul
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Emilie-Fleur Gautier
5Laboratory of Excellence Globule Rouge d’Excellence, Proteom’IC Facility, Université Paris Cité, Centre National de la Recherche Scientifique, INSERM, Institut Cochin, Paris, France
Michael Dussiot
Maria A. Lizarralde-Iragorri
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Annalisa Santini
4Laboratory of Chromatin and Gene Regulation During Development, Université Paris Cité, Imagine Institute, INSERM 1163, Paris, France
Sandy Peltier
6Laboratory of Excellence Globule Rouge d’Excellence, Université Paris Cité, INSERM, Biologie Intégrée du Globule Rouge, Paris, France
Pascal Amireault
Vanessa Soldan
Annarita Miccio
Mounia Debili
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Thiago Trovati Maciel
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Eric Allemand
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, Université Paris Cité, Institut Imagine, INSERM U1163, Paris, France
Mohammad Salma
Eric Soler
Pierre-Emmanuel Gleizes
12Biologie Moléculaire, Cellulaire et du Développement, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique, Université Toulouse 3 Paul Sabatier, Toulouse, France
Marie-Françoise O’Donohue
12Biologie Moléculaire, Cellulaire et du Développement, Centre de Biologie Intégrative, Université de Toulouse, Centre National de la Recherche Scientifique, Université Toulouse 3 Paul Sabatier, Toulouse, France
Manuel S. Rodriguez
14Laboratoire de Chimie de Coordination, Centre National de la Recherche Scientifique-Unité Propre de Recherche 8241, Toulouse, France
Olivier Hermine
Jérome Hadjadj
Rim Bourguiba
Maël Heiblig
9Department of Hematology, Centre Hospitalier Universitaire de Lyon, Lyon, France
Chloé Mc Avoy
Valentin Lacombe
Samuel Ardois
Thibault Comont
Estibaliz Lazaro
Francois Lifermann
Guillaume Le
Hervé Lobbes
Vincent Grobost
Roderau Outh
Yvan Jamilloux
Alexis Mathian
Jonathan Broner
Thomas Moulinet
Mikael Ebbo
Department of Internal Medicine, Aix-Marseille Université, Assistance Publique–Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France
Achille Aouba
François Chasset
Laurent Arnaud
Pierre Sujobert
Pierre Hirsch
Noémie Abisror
Pierre Fenaux
Olivier Kosmider
11Centre National de la Recherche Scientifique UMR8104, INSERM U1016, Institut Cochin, Université de Paris Cité, Paris, France
Vincent Jachiet
8Département Médico-Universitaire, Médecine interne, Centre de Référence des Maladies Auto-inflammatoires et des Amyloses Inflammatoire, Sorbonne Université, Hôpital Saint Antoine, Paris, France
Olivier Fain
Benjamin Terrier
1INSERM U970, Paris Centre de Recherche Cardiovasculaire, Université Paris Cité, Paris, France
Sophie Georgin-Lavialle
9Internal Medicine Department, Sorbonne University, Assistance Publique–Hôpitaux de Paris, Tenon Hospital, Paris, France
Arsène Mekinian
Lin Pierre Zhao
Maxime Samson
Antoine Neel
Holy Bezanahary
Julien Rossignol
Shanti Ame
Alexandra Audemard-Verger
Ygal Benhamou
Jean David Bouaziz