PROJECT SUMMARY

The goal of our proposal is to improve treatments for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Some people with these conditions have a mutation in a gene called TP53, and this mutation makes it harder for treatments to work. Only a small number of people with TP53 mutations respond well to current therapies, and those who do still don’t typically live very long. This project focuses on finding better ways to treat people with these TP53 mutations. Our experiments will explore the role of a protein called DNMT1, which is the target of the cancer drug decitabine and helps manage DNA replication in cells. DNMT1 may be particularly important in cells with TP53 mutations, which already have some trouble copying their DNA properly. We have discovered that both decitabine and a related drug that blocks DNMT1 (DNMT1i) can disrupt DNA from being copied in these cancer cells. However, decitabine also causes DNA damage, stops cell growth, and more effectively kills the cells. Using a CRISPR screen that allowed us to test every gene at once, we found that loss of a gene called HUWE1 made the DNMT1i capable of killing the cancer cells. We plan to investigate whether blocking HUWE1 can make these treatments more effective. This research could lead to more effective therapies for people with TP53-mutant MDS/AML, improving their chances of survival.