Targeting WT1-Mutant Stem-like Programs Driving Lineage Plasticity and Therapy Resistance in Pediatric AML
Acute myeloid leukemia (AML) is an aggressive blood cancer in children. Even with strong chemotherapy and bone marrow transplants, many children relapse, and relapse is often deadly. About one in four children in this high-risk group carries a mutation in a gene called WT1. These patients often respond poorly to treatment and relapse early, but we still do not fully understand why. WT1 normally helps guide healthy blood cell growth. When WT1 is damaged, our research shows that leukemia cells can “rewire” themselves to survive. They switch on genes to become more stem-like, and gain the ability to change their identity. These “shape shifting” leukemia stem cells can hide from therapy, stay quiet in protected areas of the bone marrow, and later grow back to cause relapse. In this project, we will use advanced tools to model WT1-mutant childhood AML using human blood stem cells. This will let us see exactly how WT1 mutations activate these dangerous survival programs. We will also test new treatment strategies that target these pathways, including drug-filled nanoparticles designed to deliver therapy directly to leukemia stem cells. Our goal is to understand why WT1-mutant leukemia is so hard to cure and to lay the groundwork for therapies that prevent relapse and give more children the chance for long, healthy lives.
Project Goals
The goal of this project is to understand why WT1-mutant childhood AML is so hard to cure and to find new ways to stop the leukemia from coming back. First, we will build accurate lab models of this high-risk leukemia by starting with healthy human blood stem cells and engineering them to carry the same genetic changes seen in children with WT1-mutant AML. This will allow us to watch how these changes turn normal cells into aggressive leukemia in a way that closely matches what happens in patients. Next, we will study how WT1 mutations change the behavior of leukemia stem cells, the rare “root” cells that can survive treatment and later regrow the disease. Our early work suggests that WT1 mutations switch on pathways that make these cells tougher, more flexible, and more resistant to therapy. We will examine how these pathways work and why they give leukemia stem cells a survival advantage. Finally, we will test new treatment strategies using our models and patient leukemia samples. These include drugs that block the harmful pathways turned on by WT1 mutations and “smart” nanoparticles designed to deliver therapy directly to leukemia stem cells. Our long-term aim is to develop combination treatments that eliminate relapse-causing leukemia stem cells, lower the chance of the leukemia returning, and ultimately improve outcomes for children with WT1-mutant AML.
