The Role of Inherited MLL3 Single Nucleotide Variants and Fetal Epigenetic Programming in Infant Leukemogenesis
Background: My goal is to improve treatments for infant leukemia patients and genetic counseling efforts for their families. To realize this goal, we will develop mouse models to study the interactions between MLL translocations (the most common mutation in infant leukemia) and inherited genetic variants that potentially predispose to infant leukemia – in this case variants in the MLL3 gene. Mice are the optimal model for these studies because they are genetically tractable and mouse blood development closely approximates human blood development.
Project Goal: We will use our mouse models to learn how genes such as MLL3 regulate blood development and leukemia development. We will use these models to identify druggable pathways that can be targeted to improve survival and reduce toxicity. To accelerate this process, we will develop a novel method to introduce the genetic variants found in human patients into the mouse genome and test whether they accelerate leukemia development. Our system will allow us to characterize interactions between many different variants without generating and breeding many different lines of mice. This will be a powerful tool to determine which genetic differences between leukemia patients and healthy children are important for leukemia development and which are inconsequential. We will build a database of functionally proven, leukemia-promoting variants that will inform cancer predisposition counseling and precision medicine. Over the long-term, I hope to expand this program to encompass other pediatric malignancies, as inherited genetic variants are becoming increasingly recognized as an underlying cause for pediatric cancer.
Project Update 2021: We have studied how mutations in a gene called MLL3 can lead to leukemias in infants and young children. We found that MLL3 controls the number of times that blood forming stem cells can divide. Furthermore, we showed that when it is mutated, leukemias can form. We have identified genetic changes that may predispose the childhood leukemia, and discovered that neonatal blood cells are uniquely susceptible to the mutations that cause infant leukemia. These observations help explain why infant leukemias are biologically different from leukemias in older children – the age of the cells matters. We have discovered mechanisms that make MLL3 mutant leukemias harder to treat than other leukemias, and we are now developing strategies to target these mechanisms.
