Understanding How Hematopoietic Developmental State Determines Oncogenic KMT2A Fusion Formation and Leukemic Potential
Andrew Young
MD, PhDWashington University in St. Louis
Project Term: July 1, 2024 - June 30, 2027
My goal is to understand how cancer-associated gene fusions arise and cause disease. Specifically, I am studying how oncogenic fusions involving the gene KMT2A arise in different hematopoietic cell-types and how developmental context drives the development of leukemia. My long-term goals are to leverage an increased fundamental understanding of leukemogenesis provided by this research to improve treatment and lengthen lifespan for patients with KMT2A fusion-driven leukemias.
Acute leukemia is a family of aggressive blood cancers that is diagnosed in 27,000 individuals and responsible for 13,000 deaths the United States each year. There is pressing clinical need to develop novel and effective therapies to treat this disease. The path to finding new therapies begins with a deep understanding of the molecular drivers of leukemia and the process of leukemia development—leukemogenesis. Chromosomal translocations (also known as fusions) are one class of genomic alterations that drive cancer—arising when there is a break in a chromosome that is inappropriately fused to a different chromosome. In this proposal, we want to understanding how one specific type of fusion—involving the KMT2A gene—forms and drives leukemia. While most cancer-causing fusions arise between the same two fusion partners, KMT2A can fuse with one of at least 80 different partners to cause leukemia. This fusion partner diversity has been known for decades, but the cause of this variation is unknown and its role in leukemogenesis is poorly understood.
We want to understand how these fusions form and drive disease. We know that the 3-D structure of DNA in the genome is highly organized and differs based on cell-type. We hypothesis that these differences drive different KMT2A fusions to form in different cell-types and that cell-type determines the likelihood of developing leukemia. We plan to test this hypothesis using DNA sequencing that preserves chromatin organization and by studying human blood cells harboring KMT2A fusions introduced by gene editing. We will also study how cell-type affects leukemia development in an in vivo model of leukemogenesis.
If successful, this study will answer fundamental questions about how KMT2A fusions form, what governs fusion partner diversity, and how cell-type drives leukemic potential. This fundamental understanding will lay the groundwork to develop therapeutic interventions to target this process. For the broader field of oncology, this work will validate a new platform to model leukemia and test novel therapeutic interventions in a rapid and reliable system. These tools are broadly applicable to any fusion driven leukemia and not limited just to studying KMT2A biology. This work will be the foundation for my career goal of translating a deeper understanding of leukemogenesis into therapeutic interventions to help our patients live longer, healthier lives.