David B. Beck, M.D.
2023 Funding recipient
Defining the Role of Global Ubiquitylation in MDS in Animal Models
Discovery Research Grant 2023
Myelodysplastic syndrome (MDS) is a common form of bone marrow failure that causes problems with the blood, increased risk of leukemia and death. Both the underlying causes and the prognosis of MDS have been linked to specific genetic changes (called mutations) and inflammation. Uncovering why these genetic mutations lead to disease can provide important insights into treatment for patients and a better understanding of why the disease occurs. We recently identified a new genetic cause of MDS with co-occurring inflammation, namely genetic mutations in the gene UBA1 leading to VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome which has led to changes in treatment, prognosis and screening for patients who carry these mutations. UBA1 is a key protein involved in regulating signals related to a tagging process called ubiquitylation, which can change cellular responses and lead to destruction of unneeded proteins. We have also identified that additional genetic mutations in genes known to be involved in blood cancer (DNMT3A and TET2), occurring at the same time as mutations in UBA1, can lead to more severe disease. Despite the fact that thousands of patients have been identified with VEXAS syndrome, and a large effort has been placed in studying patient cells, we still do not have highly effective therapies or understand why UBA1 mutations lead to disease and why only some patients develop bone marrow disease. Here we intend to extend beyond our extensive work with patient samples to test the role of UBA1 in bone marrow disease in animal models. These mouse models will allow us to investigate how genetic mutations lead to the earliest stages of disease and how the disease changes over time, something not possible in patients. We plan to extend beyond understanding UBA1 and VEXAS syndrome and determine the role of other factors in MDS formation and progression. We will characterize the effect of additional pathways on UBA1-dependent bone marrow disease using genetic mutations within DNMT3A and TET2, along with modulating inflammation. We will apply cutting edge technologies to determine which cells cause disease in these models. Together, this work will determine how UBA1 mutations lead to MDS and determine the factors contributing to disease severity, thereby shedding light on how best to treat people with VEXAS syndrome.