T cell acute lymphoblastic leukemia entry into the central nervous system

PROJECT SUMMARY Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy in children. Although the five-year survival rate for ALL has approached 90% over the last 50 years, ALL’s invasion of the central nervous system (CNS), specifically the meninges (protective membrane layers that cover the brain and spinal cord), remains a significant clinical problem. Standard-of-care treatment for every child diagnosed with ALL includes chemotherapy delivered directly into the cerebrospinal fluid, and this regimen can cause multiple serious adverse events detrimental to normal neural development. Despite efforts to explain what attracts T-ALL to the CNS, it is still unclear why ALL is commonly found in the nutrient-limited meninges. Understanding how leukemia cells infiltrate the CNS is essential to furthering the development of targeted therapies for this disease. Among the different subtypes of ALL, T cell ALL (T-ALL) has the highest tendency to present with aggressive CNS disease, so we will focus our work on T-ALL. In spite of the dogma that the CNS is an immune privileged site, lymphocytes do enter the CNS in some settings, and previous studies have identified two major routes of lymphocyte trafficking into the meninges. During inflammation, effector T cells extravasate from blood across specialized venules into the cerebrospinal fluid. More recently, myeloid cells, developing B cells and B cell ALL (B-ALL) have been found migrating from the calvarial (superior portion of the skull) bone marrow into the meninges via bridging channels. Both paths are thought to require integrins. Our proposal will address major questions that arise from this prior knowledge: 1. Do T-ALL cells traffic through bridging channels in the calvaria to seed the meninges? 2. Are integrins required for T-ALL entry into the CNS? Using novel imaging techniques, we have the unique opportunity to characterize a major route of T-ALL entry into the meninges (Aim 1). We will also determine whether or not integrins are important for T-ALL CNS infiltration (Aim 2). Results from this work will provide significant insight into the development of targeted CNS-directed therapeutics for T-ALL patients.