The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukaemia blasts

Williams, M. T.S. et al. (2016) The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukaemia blasts. Blood, 127, 16. (doi: 10.1182/blood-2015-08-665034) (PMID:26869395)

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Abstract

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

Item Type:Articles
Additional Information:This work was supported by the Kay Kendall Leukaemia Fund (KKL454, KKL515) (CH, LR) with additional funding from Cancer Research UK (C27943/A12788) (JV, OH), Leukaemia and Lymphoma Research (DM, TP, KD, PK), the European Research Council (PS), the WLBH Foundation and Chief Scientist Health Ministry ERA-NET grant (SI), the Chief Scientists’ Office (SCD/08) (CH), the Scottish Funding Council (CH) a Wellcome Trust Senior Investigator award (GG) and the Medical Research Council (G0901113, G0802259) (GG, SB).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halsey, Professor Chris and Yousafzai, Dr Yasar and Williams, Dr Mark and Graham, Professor Gerard
Authors: Williams, M. T.S., Yousafzai, Y. M., Elder, A., Rehe, K., Bomken, S., Frishman-Levy, L., Tavor, S., Sinclair, P., Dormon, K., Masic, D., Perry, T., Weston, V. J., Kearns, P., Blair, H., Russell, L. J., Heidenreich, O., Irving, J. A.E., Izraeli, S., Vormoor, J., Graham, G., and Halsey, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:11 February 2016
Copyright Holders:Copyright © 2016 American Society of Hematology
First Published:First published in Blood 127(16)
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
514422Regulation of the adaptive immune response by chemokine scavenging receptorsGerard GrahamMedical Research Council (MRC)G0901113III -IMMUNOLOGY