Journal article 144 views
T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
Nitesh D. Sharma,
Esra'a Keewan,
Wojciech Ornatowski,
Silpita Paul,
Monique Nysus,
Christopher C. Barnett,
Julie Wolfson,
Quiteria Jacquez,
Bianca L. Myers,
Huining Kang 
,
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
,
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
Swansea University Author:
Nick Jones
Full text not available from this repository: check for access using links below.
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 |
|---|---|
| ISSN: | 1558-8238 |
| Published: |
American Society for Clinical Investigation
2025
|
| Online Access: |
Check full text
|
| 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 T-ALL patients 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, TNFα, IL27 and IFNγ, 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. |
|---|---|
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
he National Cancer Institute (NCI) grant R01 CA237165 and R01 CA282701 (Matlawska)
supported this project. Matlawska is an American Cancer Society Research Scholar. Other grant
support: O’Neal Invest (Matlawska), Children’s Oncology Group Specimen Banking (U24
CA114766), (AALL15B1-Q, Matlawska); NCI Cancer Center Support Grant P30 CA013148 (UAB)
and P30 CA118100 (UNM), Dixon Foundation (Barnett), Research Foundation Flanders Ghent
University, a Flanders interuniversity consortium grant, a Cancer Research Institute Ghent (CRIG)
partnership grant (FWO G0F4721N and BOF.IBO.2023.0006.02, Ntziachristos), a Little Princess
Trust in partnership with Children’s Cancer and Leukaemia Group (CCLG) grant (CCLGA) (2020
24, Halsey; 2021 05 and 2024 08, Jones), and Cancer Research UK Programme Foundation
Award (DRCPFA-Nov21\100001, Halsey). |