Project description
Profiling the mechanisms of clonal expansion in VEXUS syndrome
VEXAS syndrome is a rare, often fatal, late-onset autoimmune disease caused by a genetic mutation in haematopoietic stem cells (HSCs). Accumulated mutations of the UBA1 gene in HSCs during aging leads to rapid multiplication of genetically identical clones (clonal expansion) from a single pro-inflammatory parent HSC. The ERC-funded ResolVE-XAS project aims to investigate the pathogenesis of VEXAS syndrome. To do so, it will determine the phenotype and genetic mutations of clones, create VEXAS models by installing mutations in human wild-type HSCs and study their impact in transplanted mice. Finally, an autologous HSC gene editing approach will support investigation of the effects of disruption or correction of UBA1 alleles.
Objective
Hematopoietic stem cells (HSCs) accumulate somatic mutations during aging, which may drive clonal expansion of their progeny. This clonal imbalance promotes cancer and often establish systemic inflammation contributing to frequent diseases of aging. Disentangling and tackling clonal imbalance of hematopoiesis is thus an urgent challenge with substantial medical implications for a progressively aging population. VEXAS syndrome is a novel, adult-onset, devastating disease with growing number of patients. It is caused by the expansion of pro-inflammatory hematopoietic clones acquiring somatic mutations of the UBA1 gene. Its pathophysiology is elusive, and treatments are unsatisfactory leading to dismal prognosis. In this project I will address knowledge gaps and unmet medical needs of VEXAS syndrome, here proposed as paradigmatic example of a hematologic disease of aging caused by clonal expansion. To unveil the uncharted pathogenesis underlying VEXAS clonal expansion and inflammation I will develop and apply to patients’ samples innovative multiomics technologies simultaneously informing on phenotype and genetic mutations of clones while reconstructing hierarchical relationships and retrospectively tracing expansion dynamics. To validate these findings in stringent settings I will leverage cutting-edge gene editing systems for the generation of VEXAS models by installing in human wild-type HSCs the pathogenic mutations found in patients, and study differentiation, clonal expansion and inflammatory properties of their outgrowth in transplanted immunodeficient mice. Finally I will investigate an autologous HSC gene editing approach in VEXAS models based on the hypothesis that targeted disruption or correction of mutant UBA1 alleles can erase fitness advantage of pathogenic clones. This project will transform current understanding and management of clonal imbalance of hematopoiesis by developing new models and technologies and proposing ambitious strategies to tackle it.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-STG
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20132 Milano
Italy
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