PROJECT SUMMARY

Myelodysplastic syndromes (MDS) are blood disorders in which the bone marrow fails to produce enough healthy blood cells, leading to fatigue, infections, and bleeding. In many people, MDS begins years earlier with clonal hematopoiesis, a condition in which a small group of altered blood stem cells gains a growth advantage and slowly expands in the bone marrow. Over time, these abnormal clones can acquire additional changes and progress toward MDS.

One of the most common early changes affects the gene DNMT3A. Although people can carry DNMT3A-mutant stem cells for years without symptoms, these clones increase the risk of later blood disease. There are currently no proven ways to safely shrink these high-risk clones before disease develops.

Our lab has identified a possible weakness in DNMT3A-mutant stem cells. These cells depend more heavily on importing amino acids, key nutrients needed for growth. We found that weakening a critical amino acid “gate” reduces the advantage of DNMT3A-mutant cells in mice while largely sparing normal stem cells.

In this project, we will define how DNMT3A alters nutrient use and test whether drugs or dietary changes that limit this pathway can safely reduce DNMT3A-mutant clones in mouse and human stem cell models. If successful, this work could lead to a new strategy to prevent or delay MDS by targeting risky clones early.