Acute lymphoblastic leukemia (ALL) is an aggressive leukemia that is most common in children and adolescents. Longterm ALL survival rates have significantly improved by the use of intensified chemotherapy and reach 80% in pediatric cases, and 60% in adult ALL, but are associated with substantial acute and long-term side effects. Moreover, the outcome of ALL patients with primary resistant or relapsed disease remains extremely poor en represents an important clinical challenge. Research from the past 10 years has identified several new targets for therapy in ALL, which can be targeted by existing small molecules. It is of high interest to study the efficacy of JAK kinase inhibitors and ABL/PDGFR inhibitors and to determine how these can be combined most effectively with current chemotherapy regimens. Additional drugs, such as BCL2 inhibitors that target apoptosis pathways way be of interest as well, as they may synergize with both chemotherapy and targeted agents. In this project we will investigate combinations of targeted therapy (Jak inhibitors, ABL/PDGFR inhibitors and BCL2 inhibitors) with chemotherapy for the treatment of primary ALL samples. We will use ex vivo cultures as well as patient derived xenograft models in immune deficient mice, which have been established by the research groups involved in this project. Careful study of the combination of these new inhibitors with chemotherapy may allow the design of less toxic treatment schedules and could increase the response to treatment for relapsed ALL patients.