2. Academic Validation
  3. Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome

Independent mechanisms of inflammation and myeloid bias in VEXAS syndrome

  • Nature. 2025 Nov 3. doi: 10.1038/s41586-025-09815-0.
Varun K Narendra # 1 2 3,  Tandrila Das # 1,  Linsey J Wierciszewski 1,  Rebecca J Londoner 1 4,  Joshua K Morrison 1 5,  Pia Martindale 1,  Tessa Devine 3,  Kevin Chen 6,  Michael Trombetta 6,  Yuzuka Kanno 1,  Alejandro E Casiano 1,  Elisa de Stanchina 6,  Caleb A Lareau 7,  Scott W Lowe 3 8,  Alexander D Gitlin 9 10 11
Affiliations

Affiliations

  • 1 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Biochemistry, Structural Biology, Cell Biology, Developmental Biology and Molecular Biology (BCMB) Allied Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA.
  • 5 Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA.
  • 6 Anti-Tumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 7 Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 8 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 9 Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • 10 Immunology and Microbial Pathogenesis Graduate Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY, USA. [email protected].
  • 11 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 41183570 DOI: 10.1038/s41586-025-09815-0
Abstract

Somatically acquired mutations in the E1 ubiquitin-activating enzyme UBA1 within haematopoietic stem and progenitor cells (HSPCs) were recently identified as the cause of the adult-onset autoinflammatory syndrome VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic)1. UBA1 mutations in VEXAS lead to clonal expansion within the HSPC and myeloid, but not lymphoid, compartments. Despite its severity and prevalence, the mechanisms by which UBA1 mutations cause multiorgan autoinflammation and haematological disease are unclear. Here we use somatic gene-editing approaches to model VEXAS-associated UBA1 mutations in primary macrophages and HSPCs. Uba1-mutant mouse macrophages exposed to inflammatory stimuli underwent aberrant apoptotic and necroptotic cell death mediated by Caspase-8 (CASP8) and RIPK3-MLKL, respectively. Accordingly, in mice challenged with TNF or LPS, the UBA1 inhibitor TAK-243 exacerbated inflammation in a RIPK3-CASP8-dependent manner. By contrast, Uba1 mutation in HSPCs induced an unfolded protein response and myeloid bias independently of RIPK3-CASP8. Mechanistically, aberrant cell death of Uba1-mutant macrophages coincided with a kinetic defect in Lys63/Met1 (that is, linear) polyubiquitylation of inflammatory signalling complexes. Collectively, our results link VEXAS pathogenesis to the pathogenesis of rarer monogenic autoinflammatory syndromes, highlight specific ubiquitin-associated defects stemming from an apical mutation in the ubiquitylation cascade and support therapeutic targeting of the inflammatory cell death axis in VEXAS.

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