Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. CLL starts in the bone marrow in a type of white blood cells called B-lymphocytes. Standard chemotherapy has been successful in treating most patients, but drugs often are not effective when a small group of leukemia cells have specific changes in their DNA. In our earlier work, we used advanced DNA sequencing and found mutations that were present in only a few leukemia cells. These mutations, which were not found by common approaches in the clinic, changed the function of a gene called TP53. The cells that had these mutations became the major leukemia population when CLL came back. To treat such high-risk patients, new drugs have been developed, which disrupt the processes that leukemia cells use to interact with their environment. Similar to resistance against chemotherapy, some cells, which may have alterations that stop the drug from working, are not killed and can result in CLL’s return. In this project, Rutgers Cancer Institute of New Jersey and the Institute of Oncology Research will work together to analyze patient samples collected during treatment in a clinical trial, and apply highly sensitive experimental approaches to thousands of single leukemia cells to develop models that help us understand how CLL cells behave and change under new therapies. We will test our results in independent groups of patients who are being treated with the same drug, with the goal of finding new ways for doctors to diagnose and treat patients.