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Leukaemia hijacks a neural mechanism to invade the central nervous system.

Publication ,  Journal Article
Yao, H; Price, TT; Cantelli, G; Ngo, B; Warner, MJ; Olivere, L; Ridge, SM; Jablonski, EM; Therrien, J; Tannheimer, S; McCall, CM; Chenn, A ...
Published in: Nature
August 2018

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood-brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin-laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2018

Volume

560

Issue

7716

Start / End Page

55 / 60

Location

England

Related Subject Headings

  • Subarachnoid Space
  • Skull
  • Receptors, Laminin
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Neoplasm Transplantation
  • Mice, SCID
  • Mice
  • Male
  • Laminin
  • Integrin alpha6
 

Citation

APA
Chicago
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MLA
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Yao, H., Price, T. T., Cantelli, G., Ngo, B., Warner, M. J., Olivere, L., … Sipkins, D. A. (2018). Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature, 560(7716), 55–60. https://doi.org/10.1038/s41586-018-0342-5
Yao, Hisayuki, Trevor T. Price, Gaia Cantelli, Brandon Ngo, Matthew J. Warner, Lindsey Olivere, Sarah M. Ridge, et al. “Leukaemia hijacks a neural mechanism to invade the central nervous system.Nature 560, no. 7716 (August 2018): 55–60. https://doi.org/10.1038/s41586-018-0342-5.
Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, et al. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 2018 Aug;560(7716):55–60.
Yao, Hisayuki, et al. “Leukaemia hijacks a neural mechanism to invade the central nervous system.Nature, vol. 560, no. 7716, Aug. 2018, pp. 55–60. Pubmed, doi:10.1038/s41586-018-0342-5.
Yao H, Price TT, Cantelli G, Ngo B, Warner MJ, Olivere L, Ridge SM, Jablonski EM, Therrien J, Tannheimer S, McCall CM, Chenn A, Sipkins DA. Leukaemia hijacks a neural mechanism to invade the central nervous system. Nature. 2018 Aug;560(7716):55–60.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

August 2018

Volume

560

Issue

7716

Start / End Page

55 / 60

Location

England

Related Subject Headings

  • Subarachnoid Space
  • Skull
  • Receptors, Laminin
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Neoplasm Transplantation
  • Mice, SCID
  • Mice
  • Male
  • Laminin
  • Integrin alpha6