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T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
,
Katherine E. Zychowski,
Stuart S. Winter ,
Mignon L. Loh,
Stephen P. Hunger,
Eliseo F. Castillo ,
Tom Taghon,
Christina Halsey,
Tou Yia Vue,
Nick Jones ,
Panagiotis Ntziachristos,
Ksenia Matlawska-Wasowska
Journal of Clinical Investigation, Volume: 136, Issue: 2, Start page: e188888
Swansea University Author:
Nick Jones
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© 2025, Sharma et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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DOI (Published version): 10.1172/jci188888
Abstract
Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 del...
| Published in: | Journal of Clinical Investigation |
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| ISSN: | 0021-9738 1558-8238 |
| Published: |
American Society for Clinical Investigation
2026
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70767 |
| Abstract: |
Infiltration of T cell acute lymphoblastic leukemia (T-ALL) into the meninges worsens prognosis, underscoring the need to understand mechanisms driving meningeal involvement. Here, we show that T-ALL cells expressing CXCR3 exploit normal T cell function to infiltrate the inflamed meninges. CXCR3 deletion hampered disease progression and extramedullary dissemination by reducing leukemic cell proliferation and migration. Conversely, forced expression of CXCR3 facilitated T-ALL trafficking to the meninges. We identified the ubiquitin-specific protease 7 as a key regulator of CXCR3 protein stability in T-ALL. Furthermore, we discovered elevated levels of CXCL10, a CXCR3 ligand, in the cerebrospinal fluid from patients with T-ALL and leukemia-bearing mice. Our studies demonstrate that meningeal stromal cells, specifically pericytes and fibroblasts, induce CXCL10 expression in response to leukemia and that loss of CXCL10 attenuated T-ALL influx into the meninges. Moreover, we report that leukemia-derived proinflammatory cytokines, TNF-α, IL-27, and IFN-γ, induced CXCL10 in the meningeal stroma. Pharmacological inhibition or deletion of CXCR3 or CXCL10 reduced T-ALL cell migration and adhesion to meningeal stromal cells. Finally, we reveal that CXCR3 and CXCL10 upregulated VLA-4/VCAM-1 signaling, promoting cell-cell adhesion and thus T-ALL retention in the meninges. Our findings highlight the pivotal role of CXCR3-CXCL10 signaling in T-ALL progression and meningeal colonization. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This work is the result of NIH funding, in whole or in part, and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central.
• The National Cancer Institute (NCI) grant R01 CA237165 and R01 CA282701 (to KMW).
• O’Neal Invest (to KMW).
• Children’s Oncology Group Specimen Banking (U24 CA114766), (AALL15B1-Q, to KMW).
• NCI Cancer Center Support Grant P30 CA013148 (UAB) and P30 CA118100 (UNM).
• Dixon Foundation (to CCB).
• Research Foundation Flanders Ghent University and Flanders interuniversity consortium grant (to PN).
• Cancer Research Institute Ghent (CRIG) partnership grant (FWO G0F4721N and BOF.IBO.2023.0006.02, to PN).
• Little Princess Trust in partnership with Children’s Cancer and Leukaemia Group (CCLG) grant (CCLGA) (2020 24, to CH; 2021 05 and 2024 08, to NJ).
• Cancer Research UK Programme Foundation Award (DRCPFA-Nov21\100001, to CH).
• American Cancer Society Research Scholar (to KMW). |
| Issue: |
2 |
| Start Page: |
e188888 |