Return of the clones: Mechanisms driving clonal evolution and relapse development in pediatric Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Improvements in the treatment made over the last decades have resulted in increased overall survival, now reaching 90%. However, around 10% of children experience disease recurrence, known as relapse, and outcome among them is poor. ALL, like other cancers, is a genetic disease caused by small changes in the DNA, known as mutations. Some of these mutations have the potential to drive disease development, as well as biological mechanisms responsible for ineffectiveness of the treatment, which can lead to relapse. In this thesis, we examined the mutational spectrum of ALL prior to relapse, and mutations that typically arise at the time of relapse. The dynamic changes observed for mutations detected at diagnosis and relapse provided us insights into the evolution of distinct populations of leukemic cells. Furthermore, we studied the impact of pathogenic mutations that are present in only a subset of the cells in order to understand their contribution for relapse development. Finally, we investigated the mechanisms that cause mutations in ALL, and identified several independent mutational mechanisms. These included mutational mechanisms driven by internal factors, such as defects in the DNA repair mechanisms, or by external factors, such as medicines commonly used in the treatment of ALL. Such mutational mechanisms can result in high mutational burden, a phenomenon known as hypermutation. Together, these novel insights in the genetic basis of relapse development will help us to improve outcome for patients with high-risk ALL.