PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are blood diseases in which the bone marrow does not work properly, causing low blood counts, fatigue, infections, and in some patients, progression to leukemia. In roughly one in three MDS patients, the disease is accompanied by serious inflammation, leading to skin rashes, joint swelling, and cartilage damage. These patients are harder to treat and have worse outcomes.

A key example is VEXAS syndrome, caused by acquired mutations in UBA1, a gene that helps cells remove damaged proteins. Our group has found that neutrophils may be the key drivers of inflammation in VEXAS and inflammatory MDS. We identified that neutrophils carrying UBA1 mutations are dramatically expanded and behave abnormally, releasing molecules that drive widespread inflammation in VEXAS. We confirmed these findings in mouse models; where loss of Uba1 in neutrophils leads to skin inflammation, cartilage damage, and low blood counts, closely mimicking human disease.In our proposed project, we will study how mutant neutrophils communicate with and damage other immune cells and the bone marrow, and test whether blocking neutrophil-driven inflammation can improve disease. We will also determine whether neutrophil dysfunction is a feature of other inflammatory MDS subtypes. This research addresses a critical unmet need for patients with inflammatory MDS who currently have few effective treatment options.