Individuals treated for cancer with chemotherapy and/or radiation can develop a blood disorder called therapy-related myelodysplastic syndrome (t-MDS). This typically occurs ~4-7 years after exposure and comprises about 20% of all MDS cases. There are at least 2,000 new cases of t-MDS in the U.S. each year and this number is expected to rise as more people survive their cancer. People with t-MDS have difficulty making blood cells. This makes them feel fatigued, bleed more readily, and/or renders them susceptible to severe infections. They frequently require blood transfusions. t-MDS can evolve rapidly into leukemia, which is often difficult to treat. Overall, people with t-MDS survive only ~8-10 months after diagnosis. The only curative treatment is bone marrow transplantation, but this is not available to all patients and is not always effective. How and why t-MDS arises is not well understood. This lack of knowledge has made it difficult to develop new ways to prevent and treat this disease. A relatively high proportion of patients (16-40%) have mutations in a gene called RUNX1. Yet, why RUNX1 mutations are so prevalent in t-MDS is not known. Our preliminary data indicate that RUNX1 works with another protein called p53 that normally guards cells against DNA damage. This proposal will investigate how RUNX1 works with p53, how RUNX1 itself is activated by DNA damage, and whether a new class of drugs that target cells with DNA damage can be used to treat t-MDS.