Acute lymphoblastic leukemia (ALL) is the most common cancer of childhood. Despite significant advances in curing ALL in most children, approximately 20% of these patients will relapse, and nearly all relapsed patients will die from their leukemias. Our research focuses upon studying blood and bone marrow samples from children with certain types of high-risk ALL with the goal of improving our understanding of the functional consequences of specific genetic mutations. In the laboratory, we investigate how pediatric ALL samples are 'miswired' through the protein communication networks within the cells and how we may disrupt faulty wiring networks with novel medications called signal transduction inhibitors (STIs). We have previously used a specialized laboratory technique called phosphoflow cytometry to examine whether or not different proteins within the wiring networks are turned 'on' within the leukemia cells following stimulation with different types of biologic signals. We are currently using specialized mouse models of childhood ALL with mutations in the CRLF2 and JAK genes to test specific STI medications which target the miswired networks in these leukemias that we identified in our earlier studies of patient samples. At the same time, we are also using phosphoflow cytometry as a biomarker to study the faulty wiring in the blood samples from children with relapsed leukemias who are enrolled on a Children's Oncology Group Phase I clinical trial of a new STI medication called a JAK inhibitor to correlate the biochemical wiring effects with patients' clinical responses. Through this work, we hope to improve our understanding of the critical biologic mechanisms involved in these leukemias and to identify new targeted STI-based therapies for children with high-risk ALL.