PROJECT SUMMARY

We are interested in a protein called DNA methyltransferase 3A (DNMT3A) that is important for the normal production of healthy blood cells. Changes, or mutations, in the DNMT3A gene are found in many blood cancers, including myelodysplastic syndrome (MDS). Importantly, DNMT3A mutations can be found in people’s blood cells many years before they develop MDS. These changes in DNMT3A cause blood stem cells, which are special cells that make all the other cells in the blood, to make many abnormal blood cells with mutant DNMT3A. This phenomenon is called clonal hematopoiesis (CH) and suggests that having DNMT3A mutations in their blood makes them more likely to get MDS. Our recent study has shown that many CH and MDS-related DNMT3A mutations are constantly being broken down at the protein level in blood cells. Based on our work, we believe that increasing the amount of DNMT3A protein could be a good way to treat and prevent CH and MDS. But we do not know exactly how DNMT3A protein is being broken down and whether stopping this process will be a helpful way to stop MDS from forming. In this proposal, our goal is to answer these important questions. These studies will enable us to find out how DNMT3A protein is broken down and to uncover which other genes and proteins might be involved in this process. If these studies are successful, we hope to develop a way to stop DNMT3A from being broken down for patients to improve outcomes for people with DNMT3A-mutant CH and MDS.