Remember Me
Or use your Academic/Social account:


You have just completed your registration at OpenAire.

Before you can login to the site, you will need to activate your account. An e-mail will be sent to you with the proper instructions.


Please note that this site is currently undergoing Beta testing.
Any new content you create is not guaranteed to be present to the final version of the site upon release.

Thank you for your patience,
OpenAire Dev Team.

Close This Message


Verify Password:
Verify E-mail:
*All Fields Are Required.
Please Verify You Are Human:

OpenAIRE is about to release its new face with lots of new content and services.
During September, you may notice downtime in services, while some functionalities (e.g. user registration, validation, claiming) will be temporarily disabled.
We apologize for the inconvenience, please stay tuned!
For further information please contact helpdesk[at]openaire.eu

fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Williams, Mark T.S.; Yousafzai, Yasar M.; Elder, Alex; Rehe, Klaus; Bomken, Simon; Frishman-Levy, Liron; Tavor, Sigal; Sinclair, Paul; Dormon, Katie; Masic, Dino; Perry, Tracey; Weston, Victoria J.; Kearns, Pamela; Blair, Helen; Russell, Lisa J.; Heidenreich, Olaf; Irving, Julie A.E.; Izraeli, Shai; Vormoor, Josef; Graham, Gerard; Halsey, Christina (2016)
Publisher: American Society of Hematology
Languages: English
Types: Article
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.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 1. Evans AE, Gilbert ES, Zandstra R. The increasing incidence of central nervous system leukemia in children. (Children's Cancer Study Group A). Cancer. 1970;26(2):404-409.
    • 2. Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257-268.
    • 3. Halsey C, Buck G, Richards S, Vargha-Khadem F, Hill F, Gibson B. The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI. J Hematol Oncol. 2011;4:42.
    • 4. Price RA, Johnson WW. The central nervous system in childhood leukemia. I. The arachnoid. Cancer. 1973;31(3):520-533.
    • 5. Pine SR, Yin C, Matloub YH, et al. Detection of central nervous system leukemia in children with acute lymphoblastic leukemia by real-time polymerase chain reaction. J Mol Diagn. 2005;7(1):127-132.
    • 6. Scrideli CA, Queiroz RP, Takayanagui OM, Bernardes JE, Melo EV, Tone LG. Molecular diagnosis of leukemic cerebrospinal fluid cells in children with newly diagnosed acute lymphoblastic leukemia. Haematologica. 2004;89(8):1013-1015.
    • 7. Martinez-Laperche C, Gomez-Garcia AM, Lassaletta A, et al. Detection of occult cerebrospinal fluid involvement during maintenance therapy identifies a group of children with acute lymphoblastic leukemia at high risk for relapse. Am J Hematol. 2013;88(5):359-364.
    • 8. Krishnan S, Wade R, Moorman AV, et al. Temporal changes in the incidence and pattern of central nervous system relapses in children with acute lymphoblastic leukaemia treated on four consecutive Medical Research Council trials, 1985-2001. Leukemia. 2010;24(2):450-459.
    • 9. Burger B, Zimmermann M, Mann G, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003;21(2):184-188.
    • 10. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14(3):199-209.
    • 11. Rehe K, Wilson K, Bomken S, et al. Acute B lymphoblastic leukaemiapropagating cells are present at high frequency in diverse lymphoblast populations. EMBO Mol Med. 2013;5(1):38-51.
    • 12. Irving J, Matheson E, Minto L, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124(23):3420-3430.
    • 13. Williams MT, Yousafzai Y, Cox C, et al. Interleukin-15 enhances cellular proliferation and upregulates CNS homing molecules in pre-B acute lymphoblastic leukemia. Blood. 2014;123(20):3116-3127.
    • 14. Halsey C, Docherty M, McNeill M, et al. The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells. J Hematol Oncol. 2012;5:45.
    • 15. Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 2009;55(4):611-622.
    • 16. McKimmie CS, Graham GJ. Astrocytes modulate the chemokine network in a pathogen-specific manner. Biochem Biophys Res Commun. 2010;394(4):1006-1011.
    • 17. Bomken S, Buechler L, Rehe K, et al. Lentiviral marking of patient-derived acute lymphoblastic leukaemic cells allows in vivo tracking of disease progression. Leukemia. 2013;27(3):718-721.
    • 18. Gabriel R, Eckenberg R, Paruzynski A, et al. Comprehensive genomic access to vector integration in clinical gene therapy. Nat Med. 2009;15(12):1431-1436.
    • 19. Price RA. Histopathology of CNS leukemia and complications of therapy. Am J Pediatr Hematol Oncol. 1979;1(1):21-30.
    • 20. Buonamici S, Trimarchi T, Ruocco MG, et al. CCR7 signalling as an essential regulator of CNS infiltration in T-cell leukaemia. Nature. 2009;459(7249):1000-1004.
    • 21. Gomez AM, Martinez C, Gonzalez M, et al. Chemokines and relapses in childhood acute lymphoblastic leukemia: A role in migration and in resistance to antileukemic drugs. Blood Cells Mol Dis. 2015;55(3):220-227.
    • 22. Den Boer ML, van Slegtenhorst M, De Menezes RX, et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. Lancet Oncol. 2009;10(2):125-134.
    • 23. le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008;14(1):47-58.
    • 24. Fehse B, Kustikova OS, Bubenheim M, Baum C. Pois(s)on--it's a question of dose. Gene Ther. 2004;11(11):879-881.
    • 25. Rongvaux A, Takizawa H, Strowig T, et al. Human hemato-lymphoid system mice: current use and future potential for medicine. Annu Rev Immunol. 2013;31:635- 674.
    • 26. Kamel-Reid S, Letarte M, Doedens M, et al. Bone marrow from children in relapse with pre-B acute lymphoblastic leukemia proliferates and disseminates rapidly in scid mice. Blood. 1991;78(11):2973-2981.
    • 27. Meyer LH, Eckhoff SM, Queudeville M, et al. Early relapse in ALL is identified by time to leukemia in NOD/SCID mice and is characterized by a gene signature involving survival pathways. Cancer Cell. 2011;19(2):206-217.
    • 28. Uckun FM, Sather H, Reaman G, et al. Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia. Blood. 1995;85(4):873-878.
    • 29. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol. 2003;3(7):569-581.
    • 30. Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337-341.
    • 31. Wu S, Gessner R, Taube T, et al. Chemokine IL-8 and chemokine receptor CXCR3 and CXCR4 gene expression in childhood acute lymphoblastic leukemia at first relapse. J Pediatr Hematol Oncol. 2006;28(4):216-220.
    • 32. Durig J, Schmucker U, Duhrsen U. Differential expression of chemokine receptors in B cell malignancies. Leukemia. 2001;15(5):752-756.
    • 33. Corcione A, Arduino N, Ferretti E, et al. Chemokine receptor expression and function in childhood acute lymphoblastic leukemia of B-lineage. Leuk Res. 2006;30(4):365-372.
    • 34. Meyer LH, Debatin KM. Diversity of human leukemia xenograft mouse models: implications for disease biology. Cancer Res. 2011;71(23):7141-7144.
    • 35. Svenningsson A, Andersen O, Edsbagge M, Stemme S. Lymphocyte phenotype and subset distribution in normal cerebrospinal fluid. J Neuroimmunol. 1995;63(1):39- 46.
    • 36. Cario G, Izraeli S, Teichert A, et al. High interleukin-15 expression characterizes childhood acute lymphoblastic leukemia with involvement of the CNS. J Clin Oncol. 2007;25(30):4813-4820.
    • 37. Krause S, Pfeiffer C, Strube S, et al. Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS). Blood. 2015;125(5):820-830.
    • 38. Holland M, Castro FV, Alexander S, et al. RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia. Blood. 2011;118(3):638-649.
    • 39. van der Velden VHJ, de Launaij D, de Vries JF, et al. New cellular markers at diagnosis are associated with isolated central nervous system relapse in paediatric B-cell precursor acute lymphoblastic leukaemia. British Journal of Haematology. 2015. doi:10.1111/bjh.13887
    • 40. Akers SM, Rellick SL, Fortney JE, Gibson LF. Cellular elements of the subarachnoid space promote ALL survival during chemotherapy. Leuk Res. 2011;35(6):705-711.
    • 41. Frishman-Levy L, Shemesh A, Bar-Sinai A, et al. Central nervous system acute lymphoblastic leukemia: role of natural killer cells. Blood. 2015;125(22):3420-3431.
  • No related research data.
  • No similar publications.

Share - Bookmark

Funded by projects

Cite this article

Cookies make it easier for us to provide you with our services. With the usage of our services you permit us to use cookies.
More information Ok