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Single-cell profiling of hematopoietic cells in VEXAS syndrome

ABSTRACT: Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort. We profiled inflammation and hematopoietic differentiation in these patients, and found activation of inflammatory gene programs particularly in marrow myeloid cells; HSPCs showed a preferred myeloid dominance. Patients had profound abnormalities in gene expression involved in pathways of inflammation, cell cycling and activation, and protein synthesis. We defined single bone marrow cells with expressed UBA1 mutations, and characterized gene expression of mutant myeloid cells as compared to that of wild-type, and observed upregulation of inflammatory pathways and immune activation; increased cell cycling might contribute to clonal dominance of UBA1 mutant cells. We were also able to profile other somatic mutations (DNMT3A) in two patients who had concurrent DNMT3A mutations at a high frequency. With coupled single cell T/B-cell receptor (TCR/BCR) sequencing, we characterized TCR and BCR repertoire in four patients, two of whom had B cell lymphocytosis. Cell-cell interaction analysis revealed enhanced interactions of myeloid cells with HSPCs, and interferons interaction with their receptors were frequent. We also performed bulk RNA sequencing of several leukemic cell lines with UBA1 knockdown, and observed upregulation of inflammatory pathways in these UBA1 knockdown cell lines. Conclusion: Our study discloses transcriptome signatures of hematopoietic cells in VEXAS syndrome, providing a broad perspective into potential pathogenesis of this novel disease.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196052 | GEO | 2023/07/18

REPOSITORIES: GEO

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Project description:Acquired mutations in the UBA1 gene, occurring in myeloid cells and resulting in expression of a catalytically impaired isoform of the enzyme E1, were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). The precise physiological and clinical impact of these mutations remains poorly defined. Here, we studied a unique prospective cohort of individuals with severe autoinflammatory disease with (VEXAS) or without (VEXAS-like) UBA1 somatic mutations and compared with low-risk myelodysplastic syndromes (MDS) and aged gender-matched healthy controls. We performed an integrated immune analysis including multiparameter phenotyping of peripheral blood leukocytes, cytokines profiling, bulk and single-cell gene expression analyses and skin tissue imaging mass cytometry. Focusing on myeloid cells, we show that monocytes from UBA1-mutated individuals were quantitatively and qualitatively impaired and displayed features of exhaustion with aberrant expression of chemokine receptors. Within affected tissues, pathological skin biopsies from VEXAS patients showed an abundant enrichment of CD16 + CD163 + monocytes adjacent to blood vessels and M1 macrophages, possibly promoting local inflammation in part through STAT3 activation. In peripheral blood from VEXAS patients, we identified a significant increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirmed the role of circulating cells in the IL-1β and IL-18 dysregulation in VEXAS patients and revealed a significant enrichment of TNF-a and NFkB signaling pathways that could mediate cell death and inflammation. Single-cell analysis confirmed the inflammatory state of monocytes from VEXAS patients and allowed us to identify specific molecular pathways that could explain monocytopenia, especially the activation of PANoptosis and a deficiency in the TYROBP/DAP12 axis and β-catenin signaling pathway. Together, these findings on monocytes from patients with UBA1 mutations provide important insights into the molecular mechanisms involving the mature myeloid commitment in VEXAS syndrome and suggest that the control of the undescribed inflammasome activation and PANoptosis could be novel therapeutic targets in this condition.

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Single-cell profiling of hematopoietic cells in VEXAS syndrome

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