Elucidation of the invasion routes of acute lymphoblastic leukemia into the central nervous system and new central nervous system prophylaxis

Abstract

Central nervous system (CNS) involvement is an important complication of acute lymphoblastic leukemia (ALL). Although intrathecal chemotherapy and high-dose systemic chemotherapy are administered to prevent the CNS involvement in ALL, CNS involvement occurs in some patients with ALL during and after chemotherapy. In addition, the meninges are a primary site of CNS involvement in ALL, but the reason why ALL cells involve the meninges is as yet unclear. It is necessary to elucidate the mechanism of the CNS involvement in ALL and to establish a new prophylaxis on the basis of this mechanism. We found that ALL cells migrate into the CNS along vessels that pass directly between the vertebral or calvarial bone marrow (BM) and the subarachnoid space. Moreover, the basement membrane of these bridging vessels is enriched with laminin, which is known to coordinate neuronal progenitor cell pathfinding in the CNS. Integrin α6, a subunit of two cell surface laminin receptors, is expressed in the majority of ALL cases. We showed that PI3Kδ inhibitors suppressed the migration of ALL cells to the CNS in ALL mouse models because integrin α6 expression is regulated by PI3Kδ. Our data suggest that ALL cells have alternative routes that are involved in the CNS, and PI3Kδ inhibitors have the potential to prevent of the CNS involvement in ALL.