Telomeres are the protective ends of chromosomes that prevent DNA damage and progressively shorten throughout life. Individuals with short telomeres are at high risk of developing blood cancers like myelodysplastic syndrome (MDS), but it is unclear how this process occurs. I have observed that patients with short telomeres frequently have blood cells that have acquired specific DNA changes, referred to as mutations, but do not have MDS yet. These blood mutations are like the seeds from which MDS may arise in the future, and the pattern of mutations can predict the risk of developing MDS. My project will determine the types of mutations that occur in patients with short telomeres and their likelihood of progressing to MDS. I will first use complementary DNA sequencing approaches to determine the number and type of mutations that occur in patients with short telomeres. I will then study how specific mutations affect the cellular response to DNA damage and telomere length in blood cells of mice with short telomeres. A deeper understanding of how blood mutations give rise to blood cancer in patients with short telomeres will improve early detection of MDS and identify novel treatments for MDS patients.