T cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges

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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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-10-23
DOI
https://doi.org/10.1172/jci188888
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
Field-Weighted Citation Impact
0.00

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article

T cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges

Tom Taghon, Mignon L. Loh, Nitesh Sharma, Christopher C. Barnett et al.
Journal of Clinical Investigation
Acute Lymphoblastic Leukemia research
article

T cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges

Tom Taghon, Mignon L. Loh, Nitesh Sharma, Christopher C. Barnett, Panagiotis Ntziachristos, Eliseo F. Castillo, Julie Wolfson, Stephen P. Hunger, Monique Nysus, Wojciech Ornatowski, Huining Kang, Ksenia Matlawska‐Wasowska, Katherine E. Zychowski, Silpita Paul, Nicholas Jones, Christina Halsey, Esra’a Keewan, Stuart S. Winter, Quiteria Jacquez, Tou Yia Vue, Bianca L. Myers
article en

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.

Journal of Clinical InvestigationVol. 136(2)
Children's Hospital of Philadelphia (US), University of New Mexico (US), Minnesota West Community & Technical College (US), University of Alabama at Birmingham (US), Ghent University (BE), Swansea University (GB), Seattle Children's Hospital (US), Cancer Research Institute Ghent (BE), Center for Neurosciences (US), Children's Minnesota (US), University of Glasgow (GB)
Cancer Research Institute, Children's Cancer and Leukaemia Group, Cancer Research UK, Fonds Wetenschappelijk Onderzoek, Universiteit Gent, Vlaamse regering, National Cancer Institute
Openalex Percentile: Top 60%
Acute Lymphoblastic Leukemia research
DOIOpen Access PDFOpenAlex
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