The Role of Germline Variants in Infant Leukemogenesis
While other types of pediatric leukemia have enjoyed tremendous improvement in survival, infants who get leukemia still have less than 50% chance of survival and survivors often suffer long term side effects from their treatment. Infant leukemia (IL) develops during pregnancy and has unique characteristics that are poorly understood. While mutations are an important feature of cancer, IL samples possess exceptionally few mutations – not enough to account for the number of cases. Rather than these acquired mutations, we have studied DNA changes that these infants are born with and believe we have identified a unique combination of genetic changes that alter normal blood development during pregnancy, causing these blood cells to more easily become leukemia. These changes occur in a family of genes that seem to control which genes turn on and off at specific times during blood development. However, which genes at which time point and what happens when mutations are introduced to the system are not understood.
In this project, we have developed a series of human cell lines that, under the right conditions in the laboratory, can be directed to develop into many different cell types, including blood. With these, we can study how each of our candidate genes alone, in combination and with the most common mutation in IL affects how these cells become blood and potentially leukemia. Further understanding with these models will allow for testing of new treatments that could be used to improve IL survival and reduce long term side effects.