Clinical evolution and pathogenesis of VEXAS syndrome - towards improved understanding of haematoinflammatory disorders (360G-Wellcome-345592_Z_26_Z)

VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory, Somatic) syndrome, is a late-onset inflammatory disease, presenting with overlapping systemic inflammation and bone marrow failure. VEXAS' causative somatic mutations in UBA1 are found in hematopoietic stem cells (HPSCs) and lead to inactivation of UBA1, which is the E1 ubiquitin activating enzyme responsible for >90% initiation of ubiquitination, an essential cellular regulatory process. VEXAS, which has prevalence of 1:4,000 men aged over 50, mimics myelodysplastic syndromes (MDS) and several age-associated inflammatory diseases such as polymyalgia rheumatica (PMR), Sweet's Syndrome and Polyarteritis Nodosa. This suggests that abnormalities in the ubiquitination pathway caused by UBA1 and related somatic mutations in HPSCs, could be driving factors in these and other age-related bone marrow failure and overlapping inflammatory conditions. My proposed study aims to characterise the clinical landscape of VEXAS syndrome; establishing its key features and unmet therapeutic needs following its discovery 6 years ago. Furthermore, I plan to characterise the role of selected UBA1 mutations on effector cell function and ubiquitination, in hope of providing novel insights into disease pathogenesis, possible future therapeutic targets, and informing future studies into age related inflammation and bone marrow failure.