The Jackson Laboratory
Project Term: January 1, 2021 - December 31, 2025
My research focuses on why and how risk of acute myeloid leukemia (AML) increases with aging. Studying naturally aged mouse models in combination with mice engineered to express mutations commonly found in human blood stem cells with aging, we are investigating whether certain inflammatory factors that increase during aging increase the risk of leukemia. My goal is to identify biomarkers to assess risk of AML development in aging individuals and define new therapeutic targets to prevent AML.
The overall challenges that our research is addressing is that there are currently no methods to predict who will develop blood cancer as they age, and we do not know how to prevent it. The specific goal of this project is to understand how and why blood cancers develop from blood stem cells during aging, in order to identify better predictive tools and preventative treatment strategies. We study a condition that develops in a large proportion of the population during aging, called clonal hematopoiesis, which increases the risk of developing blood cancer and other diseases. Clonal hematopoiesis occurs when aged blood stem cells gain mutations, or changes, in their DNA, and these mutations provide these stem cells with a growth advantage over other blood stem cells that do not carry these mutations. Our overall objective is to determine how and why these mutations cause blood stem cells to gain a growth advantage, and how these stem cells then can go on to develop into blood cancer (and why this occurs in some individuals but not others). Our research is unique because we have developed a new and innovative mouse model of clonal hematopoiesis and its progression into blood cancer that faithfully models human disease. Using this model, we have identified specific changes that occur during aging that give mutant stem cells a growth advantage. One of the changes we have identified is an increase in inflammation with aging in the bone marrow, which is where blood stem cells reside. Based on these findings, we propose to use our new mouse model to discover the other critical mutations that cause blood stem cells in clonal hematopoiesis to develop into blood cancer. We will also determine why clonal hematopoiesis occurs faster in aged compared to young mice. Finally, we will determine whether we can block development of blood cancer in our model by inhibiting chronic inflammation. The indicators for success will be that we are able to define the mechanisms that cause progression of clonal hematopoiesis to blood cancer. Beyond these current aims, the next steps for this project will then be to test these mechanisms in pre-clinical models using human blood stem cells. This knowledge will provide a fundamental basis for the development of biomarkers to allow clinicians to predict individuals with clonal hematopoiesis who are at high risk of progression to blood cancer, and to develop novel therapies to stop development of blood cancer.