Epidemiological studies have highlighted that leukemia can be considered as the most important malignancy after radiation exposure during childhood. The high risk is related to the high sensitivity of the bone marrow at young ages. Since the red bone marrow harbors hematopoietic stem and progenitor cells (HSPCs), a better understanding of the response to protons and photons of these HSPCs is warranted, particularly in the context of pediatric proton therapy (PT). The clinical application of PT is of great interest for pediatric patients due to the optimal dose distribution and the lower integral whole body dose compared to conventional x-ray radiotherapy (i.e. photon therapy), resulting in a reduction of side effects. Despite some degree of normal tissue injury is still inevitable, radiotherapy for pediatric cancer is a life-saving procedure. Currently, there is little information available on the response of HSPCs to proton therapy. In this project, radiobiological differences between proton and conventional x-ray (photons) exposure of HSPCs will be investigated together with the underlying mechanisms for the high radiosensitivity of HSPCs in vitro and in vivo. The results will help estimate HSPC damage in radiotherapy-treated children, provide opportunities to improve treatment strategies in pediatric radiotherapy and enable better secondary leukemia risk estimations for childhood cancer survivors.