Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and one of the main causes of cancer death in children and young adults. Although the treatment of ALL has been improved in the last decades, there are still patients developing drug resistance and succumbing to the disease, especially in advanced age and with severe co-morbidities. Therefore, we propose to devise new therapeutic approaches, which are more effective while less toxic. We will establish combination therapies using preclinical in vitro and in vivo experimental models, which will be translated into clinical application in the near future. We will identify novel biomarkers based on mass cytometry and circulating DNA to distinguish the true "high-risk" patient population from the "low-to-intermediate risk" group.