The Role of Germline Variants in Infant Leukemogenesis
Lay Summary: 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.
Project Goal: 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.
Project Update 2023: In my grant proposal, I laid out my plans to study combination retinoids as a possible therapy for infant leukemia. The proposal was based on our findings that mouse leukemia cells are sensitive to combination, but not individual retinoids. To expand on this, my aims included characterizing the response of human and mouse cell leukemia cell lines to retinoids, defining the molecular response in leukemia cells, and finally generating a mouse model of infant leukemia to test retinoids in the neonatal period. During the funding period, I have mainly focused on defining the molecular response to retinoids in MLL-driven leukemia. I characterized a dominant active mutant form of the retinoid X receptor that has an anti-leukemic effect via maturation and defined the gene expression changes associated with retinoid activation through drug treatment or expression of the dominant active form. In addition, I identified an interaction between the retinoid receptors and another complex of proteins used to regulate gene expression, known as the COMPASS-like complexes. Retinoids may be playing a role in a novel interplay between the 2 arms of the COMPASS-like complexes. The next steps of this work are to explore the retinoid receptor/COMPASS-like complex interaction.
