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

Mark Williams, Y Yousafzai, A Elder, K Rehe, S Bomken, L Frishman-Levy, S Tavor, P Sinclair, K Dormon, D Masic, T Perry, VJ Weston, P Kearns, LJ Russell, O Heidenreich, JA Irving, S Izraeli, J Vormoor, GJ Graham, Christina Halsey

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Abstract

Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (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 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood–cerebrospinal fluid barrier situated close 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 leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. 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 subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.
LanguageEnglish
Pages1998-2006
Number of pages9
JournalBlood
Volume127
Issue number16
DOIs
Publication statusPublished - 21 Apr 2016

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Cerebrospinal fluid
Neurology
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cerebrospinal Fluid
Blood
Central Nervous System
B-Lymphoid Precursor Cells
Infiltration
Disease Eradication
Recurrence
Tropism
Spinal Puncture
Transplants
Chemokine Receptors
Central Nervous System Diseases
Pathology

Keywords

  • central nervous system
  • lymphoblastic leukemia
  • cerebrospinal fluid
  • blood

Cite this

Williams, M., Yousafzai, Y., Elder, A., Rehe, K., Bomken, S., Frishman-Levy, L., ... Halsey, C. (2016). The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. Blood, 127(16), 1998-2006. https://doi.org/10.1182/blood-2015-08-665034
Williams, Mark ; Yousafzai, Y ; Elder, A ; Rehe, K ; Bomken, S ; Frishman-Levy, L ; Tavor, S ; Sinclair, P ; Dormon, K ; Masic, D ; Perry, T ; Weston, VJ ; Kearns, P ; Russell, LJ ; Heidenreich, O ; Irving, JA ; Izraeli, S ; Vormoor, J ; Graham, GJ ; Halsey, Christina. / The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. In: Blood. 2016 ; Vol. 127, No. 16. pp. 1998-2006.
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Williams, M, Yousafzai, Y, Elder, A, Rehe, K, Bomken, S, Frishman-Levy, L, Tavor, S, Sinclair, P, Dormon, K, Masic, D, Perry, T, Weston, VJ, Kearns, P, Russell, LJ, Heidenreich, O, Irving, JA, Izraeli, S, Vormoor, J, Graham, GJ & Halsey, C 2016, 'The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts' Blood, vol. 127, no. 16, pp. 1998-2006. https://doi.org/10.1182/blood-2015-08-665034

The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts. / Williams, Mark; Yousafzai, Y; Elder, A; Rehe, K; Bomken, S; Frishman-Levy, L; Tavor, S; Sinclair, P; Dormon, K; Masic, D; Perry, T; Weston, VJ; Kearns, P; Russell, LJ; Heidenreich, O; Irving, JA; Izraeli, S; Vormoor, J; Graham, GJ; Halsey, Christina.

In: Blood, Vol. 127, No. 16, 21.04.2016, p. 1998-2006.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The ability to cross the blood-cerebrospinal fluid barrier is a generic property of acute lymphoblastic leukemia blasts

AU - Williams, Mark

AU - Yousafzai, Y

AU - Elder, A

AU - Rehe, K

AU - Bomken, S

AU - Frishman-Levy, L

AU - Tavor, S

AU - Sinclair, P

AU - Dormon, K

AU - Masic, D

AU - Perry, T

AU - Weston, VJ

AU - Kearns, P

AU - Russell, LJ

AU - Heidenreich, O

AU - Irving, JA

AU - Izraeli, S

AU - Vormoor, J

AU - Graham, GJ

AU - Halsey, Christina

PY - 2016/4/21

Y1 - 2016/4/21

N2 - Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (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 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood–cerebrospinal fluid barrier situated close 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 leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. 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 subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.

AB - Prevention of central nervous system (CNS) relapse is critical for cure of childhood B-cell precursor acute lymphoblastic leukemia (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 of 29 diagnostic samples (79%): 2 of 2 from patients with overt CNS disease and 21 of 27 from patients thought to be CNS negative by diagnostic lumbar puncture. Histologic findings mimic human pathology and demonstrate that leukemic cells transit the blood–cerebrospinal fluid barrier situated close 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 leukemic cells. To test this, we performed serial dilution experiments which showed CNS engraftment in 5 of 6 mice after transplant of as few as 10 leukemic cells. 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 subclinical seeding of the CNS is likely to be present in most BCP-ALL patients at original diagnosis, and efforts to prevent CNS relapse should concentrate on effective eradication of disease from this site rather than targeting entry mechanisms.

KW - central nervous system

KW - lymphoblastic leukemia

KW - cerebrospinal fluid

KW - blood

U2 - 10.1182/blood-2015-08-665034

DO - 10.1182/blood-2015-08-665034

M3 - Article

VL - 127

SP - 1998

EP - 2006

JO - Blood

T2 - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -