T Cell Acute Lymphoblastic Leukemia Exploits a Neural Proinflammatory Pathway to Colonize the Meninges

Authors

• Nitesh D. Sharma, Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.
• Esra'a Keewan, Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.
• Wojciech Ornatowski, Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.
• Silpita Paul, Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
• Monique Nysus, Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.
• Christopher C. Barnett, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
• Julie Wolfson, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
• Quiteria Jacquez, College of Nursing.
• Bianca L. Myers, Department of Neurosciences
• Huining Kang, Department of Internal Medicine, University of the New Mexico, Albuquerque, New Mexico, USA.
• Katherine E. Zychowski, College of Nursing.
• Stuart S. Winter, Children's Minnesota, Minneapolis, Minnesota, USA.
• Mignon L. Loh, Seattle Children's Research Institute and the Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.
• Stephen P. Hunger, Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
• Eliseo F. Castillo, Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of New Mexico, Albuquerque, New Mexico, USA.
• Tom Taghon, Cancer Research Institute Ghent, Ghent, Belgium. Department of Diagnostic Sciences, Ghent University, Ghent, Belgium.
• Christina Halsey, Wolfson Wohl Cancer Research Centre, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
• Tou Yia Vue, Department of Neurosciences
• Nicholas Jones, Institute of Life Science, Swansea University Medical School, Swansea, Wales, United Kingdom.
• Panagiotis Ntziachristos, Cancer Research Institute Ghent, Ghent, Belgium. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
• Ksenia Matlawska-Wasowska, Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA. Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico, USA.

Document Type

Article

Publication Date

1-16-2026

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.

Recommended Citation

Sharma ND, Keewan E, Ornatowski W, Paul S, Nysus M, Barnett CC, Wolfson J, Jacquez Q, Myers BL, Kang H, Zychowski KE, Winter SS, Loh ML, Hunger SP, Castillo EF, Taghon T, Halsey C, Vue TY, Jones N, Ntziachristos P, Matlawska-Wasowska K. T cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges. J Clin Invest. 2025 Oct 23;136(2):e188888. doi: 10.1172/JCI188888. PMID: 41129238; PMCID: PMC12807478.