One of the main challenges in identifying effective therapeutic targets for aplastic anemia and Myelodysplastic syndromes is a lack of understanding of which genes to target. Patients with AA and MDS have mutations in many different genes and the path through which the disease progresses can vary greatly between individuals. A better understanding of which genes are deregulated early in disease progression will lead to the development of more effective therapies. Recent studies have shown that genes involved in the spliceosome are often mutated in MDS. These mutations are thought to arise early, most likely in the blood-forming stem cells that give rise to all mature blood cells. The spliceosome is a large complex that is important for making sure genes are built correctly, which means that changes to the spliceosome can impact a large number of downstream factors.
Our work involves using zebrafish to study how the spliceosome regulates blood-forming stem cells. The zebrafish provides a valuable scientific model to help understand human disease as almost all genes involved in human disease have an equivalent gene in zebrafish. Additionally, zebrafish embryos are transparent, small, and easy to manipulate, which allows for relatively easy large-scale screens to identify the function of genes important for blood cell development.
To address the role of the spliceosome in blood-forming stem cells, we study zebrafish that have a mutation in a spliceosomal gene commonly mutated in MDS (sf3b1). The aim of our research is to understand what happens to these stem cells and their downstream mature blood cells when sf3b1 is mutated. A better understanding of how the spliceosome regulates hematopoiesis in development will help us elucidate what might be happening in MDS, and lead to the development of more effective therapies.