Central nervous system involvement in acute lymphoblastic leukemia

Abstract

It is well known that acute lymphoblastic leukemia (ALL) cells can invade the central nervous system (CNS), but the underlying mechanism of such invasion is still unclear. We discovered the direct routes taken by ALL cells when migrating into CNS in ALL model mice. We observed that ALL cells migrate along the external surface of vessels that pass directly between the vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin. The laminin is recognized by integrin α6, which is expressed by ALL cells. The interaction between integrin α6 and laminin mediated the invasion of ALL cells. Furthermore, the expression of integrin α6 depends on PI3Kδ activity. Mice with ALL xenografts were treated with a PI3Kδ inhibitor, which decreased integrin α6 expression on ALL cells. This resulted in significant reductions in blast counts in the cerebrospinal fluid and in CNS disease symptoms. Our data suggest that the PI3Kδ inhibitor has potential to prevent CNS involvement in ALL.