BSLD-03 T CELL ACUTE LYMPHOBLASTIC LEUKEMIA ENTRY INTO THE CENTRAL NERVOUS SYSTEM

Abstract Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy in children. Due to ALL’s tendency to invade the central nervous system (CNS), specifically the membrane layers surrounding the brain and spinal cord known as the meninges, standard-of-care treatment includes intrathecal therapy. This can be detrimental to normal neural development, and is not always effective. Among the different subtypes of ALL, our lab focuses on T cell ALL (T-ALL) because it has the highest propensity for aggressive CNS disease. It remains unclear why T-ALL is attracted to the nutrient-limited meninges. Understanding how leukemia cells infiltrate the CNS is essential to furthering the development of targeted therapies for this disease. Recently, B cell ALL (B-ALL) has been shown entering the CNS via skull bridging channels. In addition, effector T cells breach the blood-brain barrier during inflammation. Both of these entry routes require integrins. This raises the question of whether T-ALL uses one of these routes to infiltrate the CNS, and if integrins are required. Using multi-photon and confocal microscopy to visualize the skull and meninges of mice that received Notch1-driven murine T-ALL, we are characterizing a major route of T-ALL entry into the CNS. At early timepoints of disease, we find T-ALL primarily in small clusters in an area of the meninges that lies beneath the occipital region of the skull. Since this is a concentrated area of skull bone marrow, we are investigating whether the T-ALL clusters reflect cells that have recently entered the CNS via bridging channels. We plan to examine what dictates the choice of channels used, and study the directionality of T-ALL movement. In addition, we are using CRISPR to examine the effect of integrin loss on T-ALL CNS infiltration. This work will advance the development of targeted therapeutics for limiting CNS dissemination of T-ALL.