Preprint: transposable element activation implicated in VEXAS syndrome stem cell pathology

A preprint posted to bioRxiv describes new findings about the molecular mechanisms underlying VEXAS syndrome, a severe and largely treatment-refractory autoinflammatory condition caused by somatic mutations in the X-linked gene UBA1. The condition — which stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic — was only described in 2020 and affects predominantly older men.

The research team moved beyond gene-centric analysis to examine the non-coding genome, specifically the expression of individual transposable element loci in UBA1-mutant haematopoietic stem cells (HSCs). Using advanced functional genetic methods, they found that VEXAS HSCs displayed altered expression of specific transposable element loci compared with controls, and that this dysregulation may contribute to the proteostasis defects, sustained inflammation, and myeloid-biased clonal expansion that characterise the condition at the stem cell level.

The authors argue that the transposable element layer of the genome — long treated as non-functional 'junk' — may be a meaningful contributor to haematological disease pathophysiology, particularly in conditions driven by somatic mutations acquired in ageing stem cell compartments.

This is a preprint and has not yet been peer-reviewed. Findings should be treated as preliminary pending independent scrutiny and formal publication.