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; Nicholas Jones; Panagiotis Ntziachristos; Ksenia Matlawska-Wasowska

doi:10.1172/JCI188888

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

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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, …

The Journal of clinical investigation, Vol.136(2), e188888

01/16/2026

DOI: 10.1172/JCI188888

PMCID: PMC12807478

PMID: 41129238

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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.

Inflammation

Oncology

Leukemias

Cell migration/adhesion

Chemokines

Details

Title: Subtitle: T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
Creators: Nitesh D Sharma - University of Alabama at Birmingham
Esra'a Keewan - University of New Mexico
Wojciech Ornatowski - University of Alabama at Birmingham
Silpita Paul - University of Alabama at Birmingham
Monique Nysus - University of New Mexico
Christopher C Barnett - University of Alabama at Birmingham
Julie Wolfson - University of Alabama at Birmingham
Quiteria Jacquez - University of New Mexico
Bianca L Myers - University of New Mexico
Huining Kang - University of New Mexico
Katherine E Zychowski - University of New Mexico
Stuart S Winter - Children's Minnesota
Mignon L Loh - Seattle Children's Hospital
Stephen P Hunger - Children's Hospital of Philadelphia
Eliseo F Castillo - University of New Mexico
Tom Taghon - Cancer Research Institute Ghent
Christina Halsey - University of Glasgow
Tou Yia Vue - University of New Mexico
Nicholas Jones - Swansea University
Panagiotis Ntziachristos - Cancer Research Institute Ghent
Ksenia Matlawska-Wasowska - University of Alabama at Birmingham
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.136(2), e188888
DOI: 10.1172/JCI188888
PMID: 41129238
PMCID: PMC12807478
NLM abbreviation: J Clin Invest
ISSN: 1558-8238
eISSN: 1558-8238
Publisher: AMER SOC CLINICAL INVESTIGATION INC; ANN ARBOR
Grant note: NIH National Cancer Institute (NCI): R01 CA237165, R01 CA282701 Children's Oncology Group Specimen Banking: U24 CA114766, AALL15B1-Q, P30 CA118100 Dixon Foundation Research Foundation Flanders Ghent University and Flanders interuniversity consortium grant Cancer Research Institute Ghent (CRIG): FWO G0F4721N, BOF.IBO.2023.0006.02 Children's Cancer and Leukaemia Group (CCLG) grant (CCLGA): 2020 24, 2021 05, 2024 08 Cancer Research UK Programme Foundation Award: DRCPFA-Nov21\100001
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. center dot The National Cancer Institute (NCI) grant R01 CA237165 and R01 CA282701 (to KMW) . center dot O'Neal Invest (to KMW) . center dot Children's Oncology Group Specimen Banking (U24 CA114766) , (AALL15B1-Q, to KMW) . center dot NCI Cancer Center Support Grant P30 CA013148 (UAB) and P30 CA118100 (UNM) . center dot Dixon Foundation (to CCB) . center dot Research Foundation Flanders Ghent University and Flanders interuniversity consortium grant (to PN) .. center dot Cancer Research Institute Ghent (CRIG) partnership grant (FWO G0F4721N and BOF.IBO.2023.0006.02, to PN) . center dot 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) . center dot Cancer Research UK Programme Foundation Award (DRCPFA-Nov21\100001, to CH) . center dot American Cancer Society Research Scholar (to KMW) .
Language: English
Electronic publication date: 10/23/2025
Date published: 01/16/2026
Academic Unit: Stead Family Department of Pediatrics; Hematology/Oncology
Record Identifier: 9985016524802771

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