VEXAS is characterised by predominantly rheumatic and haematologic systemic involvement, and caused by somatic mutation in UBA1 – a gene encoding ubiquitin-activating enzyme 1,1,2 which is necessary for a post-translation modification that affects protein functions ranging from degradation to subcellular localisation and kinase activation.3 The syndrome was first described in 2020, but diagnosis can be challenging as the symptoms overlap with many other inflammatory conditions.1 Hot on the heels of this recent discovery, research is underway to better understand pathogenesis, clinical features, and potential treatment options.1
To support this, 6 patients were recruited from the IRCCS San Raffaele Hospital in Milan, Italy. The variant allele frequency of UBA1 mutant cells was quantified, and multiparametric immunophenotypic analysis and single cell RNA sequencing were performed on peripheral blood and bone marrow, focusing on hematopoietic stem/progenitor cells (HSPC). The results were compared to those from healthy age- and sex-matched controls. Additionally, to introduce UBA1 mutations and develop VEXAS models in healthy human HSPC, the group used cutting-edge gene-editing technologies.
Targeted sequencing supported a myeloid skewing of mutant HSPC in VEXAS patients, and multiparametric immunophenotypic analyses showed unbalanced HSPC composition in bone marrow, with 2- to 3-fold reduction of primitive stem cells, multipotent, and lymphoid progenitors – and 2-fold increase in myeloid progenitors – compared to matched healthy individuals. HSPC, myeloid-biased HSPC, and immature myeloid cells were increased by 3- to 4-fold in the circulation. Gene expression analysis of circulating monocytes displayed upregulation of inflammatory pathways and metabolic rewiring. Further metabolomic analyses confirmed hyperactivation of the glycolytic pathway and specific lipid metabolism.
The results from the single-cell RNA sequencing of bone marrow mononuclear cells identified a subpopulation of CD34+ cells specific to VEXAS patients – and revealed upregulated stress response and immune activation pathways across VEXAS cell clusters as compared to healthy controls.
In the VEXAS models, transplantation of gene-edited HSPC in immunodeficient mice resulted in a 100-fold reduction in circulating B cells, while NK and myeloid compartments were preserved.
The group conclude that mutations in UBA1 drive expansion of HSPC and enhance myelopoiesis-guided accumulation of myeloid precursors. The success of the new gene-editing models hold promise, and could be used in preclinical testing and validation of novel therapeutics for this rare disease.
Source
Campochiaro C, et al. Unraveling pathophysiology and hematopoiesis of VEXAS syndrome by multi-omics analysis and targeted gene editing. Presented at EULAR 2024; OP0073.
Ann Rheum Dis 2024; DOI: 10.1136/annrheumdis-2024-eular.3532.
References
1. Kobak S. VEXAS syndrome: Current clinical, diagnostic and treatment approaches. Intractable Rare Dis Res 2023;12(3):170–9.
2. Poulter JA, et al. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood 2021;137:3676–81.
3. Guo HJ, et al. Biochemistry, Ubiquitination. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK556052/
About EULAR
EULAR is the European umbrella organisation representing scientific societies, health professional associations and organisations for people with rheumatic and musculoskeletal diseases (RMDs). EULAR aims to reduce the impact of RMDs on individuals and society, as well as improve RMD treatments, prevention, and rehabilitation. To this end, EULAR fosters excellence in rheumatology education and research, promotes the translation of research advances into daily care, and advocates for the recognition of the needs of those living with RMDs by EU institutions.
