BSLD-09 EXPLORING THE ROLE OF CXCL12 IN T CELL ACUTE LYMPHOBLASTIC LEUKEMIA INFILTRATION OF THE CENTRAL NERVOUS SYSTEM

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer worldwide. ALL frequently disseminates to the central nervous system (CNS), specifically to the meninges surrounding the brain parenchyma and spinal cord. As a result, standard-of-care treatment includes prophylactic intrathecal chemotherapy, which can have adverse effects on neural development. T cell ALL (T-ALL) has the highest propensity for aggressive CNS disease in comparison to other ALL subtypes. It remains unclear why T-ALL is attracted to this nutrient-poor environment. Using a murine NOTCH1-driven T-ALL line, we find T-ALL clustering in a part of the meninges that lies beneath the occipital region of the skull in early disease. Since the occipital region of the skull has a high density of bone marrow, and of bridging channels connecting the bone marrow to the meninges, we are investigating whether these early clusters are composed of cells that recently migrated from the skull bone marrow via bridging channels. In addition, we are examining molecular signals that may guide T-ALL trafficking through these channels. Recent work has shown that meningeal fibroblasts are an abundant source of CXCL12, a chemokine well-known for its role in cell survival and migration. By utilizing multi-photon and confocal microscopy, we are studying the effect of loss of CXCR4, the receptor for CXCL12, on T-ALL CNS infiltration. This work will advance the development of targeted therapeutics for limiting CNS dissemination of T-ALL.