Understanding the link between bone marrow failure and chronic inflammation through the lens of VEXAS syndrome

As we age, the bone marrow becomes less effective in producing cells within the blood and the immune system. In part, this is due to changes that occur with age in the genetic make-up of bone marrow cells. Despite these genetic changes not uniformly driving a robust and homogenous disease phenotype, the functional alterations in various immune cells lead to systemic effects on blood cell production and the ability of the immune system to respond to challenges. As a result, individuals can become less able to fight infection and more likely to produce damaging levels of inflammation in a process frequently referred to as "inflammageing".

Although inflammageing has been linked to many chronic diseases, we do not fully understand exactly how specific genetic changes in the bone marrow are linked to inflammation. This is where the study of conditions such as VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is critical. This syndrome is a newly discovered disorder in which affected individuals can suffer bone marrow failure and severe inflammation in the context of a specific change in the genetic code of blood stem cells and their immune cell progeny. In the majority of cases, the genetic mutation occurs in UBA1, a molecule that controls several important cell functions including inflammation. Because of this clear link between a specific genetic change, bone marrow failure and inflammation, we can use VEXAS syndrome to understand these relationships in more detail and develop new laboratory tests to track disease evolution and identify therapeutic options. The knowledge we will gain by studying VEXAS syndrome will help improve our overall understanding of inflammageing and how this process contributes to the development of other common chronic age-related disorders.

Several population-based studies have identified links between age related bone marrow changes, such clonal haematopoiesis (CH) and various chronic inflammatory and non-inflammatory diseases. CH is a premalignant bone marrow state defined by the acquisition and outgrowth of driver mutations associated with leukaemia, leading to a clonally expanded haematopoietic stem cell (HSC) pool. The precise molecular mechanisms of the pathological low-grade sterile inflammation or "inflammageing" that has been linked to CH remains poorly characterised. The recently discovered VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome represents a unique opportunity to break open this field as it is a prototypic late-onset haematoinflammatory disorder caused by loss of function variants in a single gene (UBA1), making it an ideal condition to study the molecular mechanisms of age-related bone marrow dysfunction and associated inflammageing.

As a national referral centre, we have unique access to well-characterised cohort of VEXAS patients and patients with related conditions allowing us to perform an in-depth study of VEXAS syndrome and provide important insights into the links between acquired bone marrow failure and wider immune cell dysfunction. We will characterise the cellular and molecular pathogenesis with the longterm goal of improving diagnosis and management of VEXAS syndrome by defining the breadth of clinical phenotypes associated with novel UBA1 variants, identifying potential diagnostic and prognostic biomarkers, and by finding novel treatment targets. Our findings will not only be directly relevant to bone marrow dysfunction in the context of systemic inflammation in VEXAS, but also to a broad range of age-related chronic disorders.