Leukaemia hijacks a neural mechanism to invade the central nervous system.
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Breast cancer cells express ST6GALNAC5, which is normally exclusively expressed in the brain, allowing for increased adhesion to brain endothelial cells to pass through the BBB, and acute lymphoblastic leukemia cells access the CNS via vascular channels that exist between bone marrow located in the vertebral and calvarium bone and the meninges.
“breast cancer cells express ST6GALNAC5, which is normally exclusively expressed in the brain, allowing for increased adhesion to brain endothelial cells to pass through the BBB”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Yao et al., 2018
Cancer cells may enter the meninges via the choroid plexus, the brain, by crossing pial blood vessels or by vascular channels that connect the bone marrow and meninges.
“Cancer cells may enter the meninges via the choroid plexus, the brain, by crossing pial blood vessels or by vascular channels that connect the bone marrow and meninges”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Yao et al., 2018
During acute lymphoblastic leukemia, lymphocytes use α6-integrins to enter the leptomeninges by migrating in the perivascular space along diploic and emissary veins that run through the skull bone.
“During acute lymphoblastic leukemia, lymphocytes use α6-integrins to enter the leptomeninges by migrating in the perivascular space along diploic and emissary veins that run through the skull bone.”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [96]
Acute lymphoblastic leukemia cells never traverse the BBB but do enter the subarachnoid space.
“These cancer cells never traverse the BBB but do enter the subarachnoid space (96).”
From The anatomy and immunology of vasculature in the central nervous system (2019) · cites this paper as [96]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 32 · Cited by 264
Research works printed but not linked: 2
- [16]Belkin AM & Stepp MA Integrins as receptors for laminins. Microsc Res Tech 51, 280– 301 (2000). 11054877
- [25]Price RA & Johnson WW The central nervous system in childhood leukemia: I. The arachnoid. Cancer 31, 520– 533 (1973). 4511909
- Authors
- Yao, H., Price, T. T., Cantelli, G., Ngo, B., Warner, M. J., Olivere, L., Ridge, S. M., Jablonski, E. M., Therrien, J., Tannheimer, S., McCall, C. M., Chenn, A., & Sipkins, D. A.
- Affiliations
- Duke University (US)
- Northwestern University (US)
- Gilead Sciences (United States) (US)
- LabCorp (United States) (US)
- Corresponding author
- Sipkins, Dorothy A.
- Venue
- Nature
- Published
- 2018-07-18
- Volume
- 560
- Issue
- 7716
- Pages
- 55-60
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC10257142
- OpenAlex
- W2883104324
- Cited by
- 264
- References
- 32
- Citations by year
- 2026: 24 · 2025: 37 · 2024: 31 · 2023: 33 · 2022: 42 · 2021: 35 · 2020: 29 · 2019: 27 · 2018: 6
- FWCI
- 23.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Gilead Sciences
- Nature
- National Cancer Institute (P30CA014236)
- Duke Cancer Institute
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- acute lymphoblastic leukemia, central nervous system metastasis, CD49f, laminin, blood-brain barrier, cerebrospinal fluid, PI3Kδ inhibitor
- MeSH terms
- Animals, Basement Membrane, Blood-Brain Barrier, Bone Marrow, Cell Movement, Central Nervous System, Cerebrospinal Fluid, Cerebrovascular Circulation, Female, Laminin, Male, Neoplasm Transplantation, Skull, Subarachnoid Space, Mice, SCID, Receptors, Laminin, Disease Progression, Integrin alpha6, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Antibodies, Neutralizing, Class I Phosphatidylinositol 3-Kinases, Heterografts
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
