Grant: Project Grant

Shwachman Diamond syndrome (SDS) is a type of bone marrow failure that frequently presents in children and young adults. It results in poor growth, reduced production of white blood cells and pancreatic dysfunction. SDS is caused by abnormalities in genes, including one called DNAJC21, which play important roles in assembling ribosomes that are required in all cells to make proteins. SDS patients are at a much higher risk of developing high-risk types of leukemia. Current definitive treatment for SDS requires a bone marrow transplant and is associated with many potential complications and risks. There is an unmet need for developing treatments that are specific to SDS biology that could help restore normal blood cell numbers with the goal of preventing the development of leukemia. The zebrafish has very similar but more rapid blood development than humans, making it an ideal animal model for studying SDS and how it evolves into leukemia. Our laboratory has extensive experience in this area, and we have already developed zebrafish carrying mutations in the zebrafish DNAJC21 gene. These mutant fish have stunted growth and reduced white blood cell production similar to SDS patients. To model leukemia progression, we have introduced additional mutations in genes frequently seen in SDS patients with leukemia. We believe that the metabolism level of these blood cells is low when the bone marrow isn't working well and becomes high when it develops into leukemia. We will investigate if these metabolic factors can be targeted to stop leukemia progression. Lastly, we will use cells from SDS patients to check for the genetic changes that we find in our zebrafish and look for drugs that can rescue blood defects and potentially halt the development of leukemia. This study will improve our understanding of SDS and other conditions that increase the risk of developing leukemia and identify drugs for leukemia prevention.