PROJECT SUMMARY

As people age, blood stem cells in the bone marrow can acquire DNA mutations. In some cases, these mutations allow certain cells to grow faster than normal, a condition called clonal hematopoiesis. While often harmless, some mutations—such as those in the IDH2 gene—can increase the risk of serious blood disorders like myelodysplastic syndromes (MDS), which can progress to leukemia. Currently, there are no treatments to prevent this progression.

Our research focuses on the bone marrow environment where blood cells develop. We found that immune cells called macrophages can also carry IDH2 mutations. Instead of protecting the body, these mutated macrophages create an inflammatory environment that harms normal stem cells and allows mutant cells to take over.

We discovered that this process is driven by mitochondria, the cell’s energy producers. When disrupted, mitochondria generate harmful molecules called reactive oxygen species (ROS). These molecules damage mitochondrial DNA, causing it to leak and trigger chronic inflammation in the bone marrow.

In this project, we will identify the signals driving this inflammation and test whether blocking them can reduce ROS and protect healthy stem cells. Using patient-derived cells and disease models, our goal is to develop new strategies to prevent mutant cells from dominating the bone marrow.

If successful, this work could lead to new treatments that slow or prevent disease progression in patients with IDH2 mutations.