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Hisayuki Yao, Trevor T. Price, Matthew J. Warner, Gaia Cantelli, Lindsey Olivere, Brandon Ngo, Sarah Ridge, Joe Therrien, Stacey Tannheimer, Chad McCall, Anjen Chenn & Dorothy A. Sipkins, Acute lymphoblastic leukemia cells invade the central nervous system by secret paths to avoid blood brain barrier, 日本血液学会, 2018.10, Acute lymphoblastic leukemia (ALL) cells are well known to tend to metastasize to the central nervous system (CNS). Compared to brain metastases of solid tumors, ALL seldom involve the brain parenchyma but is isolated to the leptomeninges. While CNS metastasis is characteristic of all subtypes of ALL, a unifying mechanism for invasion has not been determined. Here we show that ALL cells in circulation are unable to breach the blood brain barrier; instead they migrate into the CNS along vessels that passage directly between the meninges en route through the adjacent skull or vertebral bodies to bone marrow (BM). The basement membrane of these bridging vessels is enriched in laminin, known to coordinate neuronal progenitor cell pathfinding in the CNS. α6 integrin, a subunit of two cell surface laminin receptors, is expressed in most of ALL cases. We found that both α6 and laminin were required for ALL migration toward cerebrospinal fluid (CSF) in in vitro invasion assays. The inhibition of PI3Kδ signaling that blocks MLCK-mediated chemotaxis also decreased α6 integrin expression of ALL cells and inhibited cell migration toward CSF along laminin. ALL-xenografted mice treated with either the PI3Kδ inhibitor or with specific α6 neutralizing antibodies showed a significant decrease in ALL transit along bridging vessels, in CSF blast counts and CNS disease symptoms despite equivalent BM disease burden compared to vehicle-treated mice. Further, immunohistochemical staining of ALL patient bone marrow biopsies for alpha6 integrin have shown a correlation between the degree of alpha6 expression and occurrence of CNS relapse. Our data suggest that expression of α6 integrin, common in ALL, allows cells to coopt neural migratory pathways to invade the CNS.. |
