PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are disorders where bone marrow fails to produce enough mature, functional blood cells, leading to a risk of aggressive, often fatal leukemia. MDS is thought to develop from clonal hematopoiesis (CH), an asymptomatic condition where blood stem cells acquire genetic mutations that give them a growth advantage. One common mutation in CH and MDS disables the TET2 gene, which plays an important role in regulating how genes are turned on and off. The role of TET2 mutations in the cell growth advantage and MDS is not fully understood, and there are no treatments to prevent CH from progressing to MDS. The only potential cure is a stem cell transplant, which is not an option for many patients.

We believe TET2 mutations alter blood stem cell function by turning key genes on or off, allowing mutant cells to outcompete healthy ones. Our research aims to understand how TET2 mutations affect blood stem cells and identify vulnerabilities that can be targeted with drugs. We will investigate and test a panel of drugs on TET2-mutated cells to find those that slow growth or encourage maturation into healthy cells. Promising drugs will be tested in mouse models of CH and MDS, and we will investigate why some cells resist treatment.

This research could lead to early treatments to prevent MDS from developing from CH or improve therapies for TET2-mutated MDS, potentially improving patient outcomes and guiding early intervention.