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Publisher: American Society of Hematology
Languages: English
Types: Article
Subjects:
Prevention of central nervous system (CNS) relapse is critical for cure of childhood Bcell\ud precursor acute lymphoblastic leukaemia (BCP-ALL). Despite this, mechanisms of\ud CNS infiltration are poorly understood and the timing, frequency and properties of\ud BCP-ALL blasts entering the CNS compartment are unknown. We investigated the\ud CNS-engrafting potential of BCP-ALL cells xenotransplanted into immunodeficient\ud NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. CNS engraftment was seen in 23/29 diagnostic\ud samples (79%), 2/2 from patients with overt CNS disease and 21/27 (78%) from\ud patients thought to be CNS-negative by diagnostic lumbar puncture. Histological\ud findings mimic human pathology and demonstrate that leukaemic cells primarily transit\ud the blood-cerebrospinal-fluid barrier sitting in close proximity to the dural sinuses – the\ud site of recently discovered CNS lymphatics. Retrieval of blasts from the CNS showed\ud no evidence for chemokine receptor-mediated selective trafficking. The high frequency\ud of infiltration and lack of selective trafficking led us to postulate that CNS tropism is a\ud generic property of leukaemic cells. To test this we performed serial dilution\ud experiments, CNS engraftment was seen in 5/6 mice following transplantation of as few\ud as 10 leukaemic cells. Finally, clonal tracking techniques confirmed the polyclonal\ud nature of CNS infiltrating cells with multiple clones engrafting in both the CNS and\ud periphery. Overall, these findings suggest that sub-clinical seeding of the CNS is likely\ud to be present in the majority of BCP-ALL patients at original diagnosis and efforts to\ud prevent CNS relapse should concentrate on augmenting effective eradication of disease\ud from this site, rather than targeting entry mechanisms.
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