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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 Orcid Logo, Katherine E. Zychowski, Stuart S. Winter Orcid Logo, Mignon L. Loh, Stephen P. Hunger, Eliseo F. Castillo Orcid Logo, Tom Taghon, Christina Halsey, Tou Yia Vue, Nick Jones Orcid Logo, Panagiotis Ntziachristos, Ksenia Matlawska-Wasowska

Journal of Clinical Investigation

Swansea University Author: Nick Jones Orcid Logo

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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...

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Published in: Journal of Clinical Investigation
ISSN: 1558-8238
Published: American Society for Clinical Investigation 2025
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URI: https://cronfa.swan.ac.uk/Record/cronfa70767
first_indexed 2025-10-24T15:13:07Z
last_indexed 2025-11-21T18:10:16Z
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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, TNF&#x3B1;, IL27 and IFN&#x3B3;, 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.</abstract><type>Journal Article</type><journal>Journal of Clinical Investigation</journal><volume>0</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>American Society for Clinical Investigation</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1558-8238</issnElectronic><keywords/><publishedDay>23</publishedDay><publishedMonth>10</publishedMonth><publishedYear>2025</publishedYear><publishedDate>2025-10-23</publishedDate><doi>10.1172/jci188888</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><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&#x2019;Neal Invest (Matlawska), Children&#x2019;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&#x2019;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).</funders><projectreference/><lastEdited>2025-11-20T15:49:27.4446031</lastEdited><Created>2025-10-24T16:12:13.8846893</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Biomedical Science</level></path><authors><author><firstname>Nitesh D.</firstname><surname>Sharma</surname><order>1</order></author><author><firstname>Esra'a</firstname><surname>Keewan</surname><order>2</order></author><author><firstname>Wojciech</firstname><surname>Ornatowski</surname><order>3</order></author><author><firstname>Silpita</firstname><surname>Paul</surname><order>4</order></author><author><firstname>Monique</firstname><surname>Nysus</surname><order>5</order></author><author><firstname>Christopher C.</firstname><surname>Barnett</surname><order>6</order></author><author><firstname>Julie</firstname><surname>Wolfson</surname><order>7</order></author><author><firstname>Quiteria</firstname><surname>Jacquez</surname><order>8</order></author><author><firstname>Bianca L.</firstname><surname>Myers</surname><order>9</order></author><author><firstname>Huining</firstname><surname>Kang</surname><orcid>0000-0002-4415-3573</orcid><order>10</order></author><author><firstname>Katherine E.</firstname><surname>Zychowski</surname><order>11</order></author><author><firstname>Stuart S.</firstname><surname>Winter</surname><orcid>0000-0003-3583-7727</orcid><order>12</order></author><author><firstname>Mignon L.</firstname><surname>Loh</surname><order>13</order></author><author><firstname>Stephen P.</firstname><surname>Hunger</surname><order>14</order></author><author><firstname>Eliseo F.</firstname><surname>Castillo</surname><orcid>0000-0002-5083-560x</orcid><order>15</order></author><author><firstname>Tom</firstname><surname>Taghon</surname><order>16</order></author><author><firstname>Christina</firstname><surname>Halsey</surname><order>17</order></author><author><firstname>Tou Yia</firstname><surname>Vue</surname><order>18</order></author><author><firstname>Nick</firstname><surname>Jones</surname><orcid>0000-0003-4846-5117</orcid><order>19</order></author><author><firstname>Panagiotis</firstname><surname>Ntziachristos</surname><order>20</order></author><author><firstname>Ksenia</firstname><surname>Matlawska-Wasowska</surname><order>21</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2025-11-20T15:49:27.4446031 v2 70767 2025-10-24 T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2025-10-24 MEDS 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. Journal Article Journal of Clinical Investigation 0 American Society for Clinical Investigation 1558-8238 23 10 2025 2025-10-23 10.1172/jci188888 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 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). 2025-11-20T15:49:27.4446031 2025-10-24T16:12:13.8846893 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Nitesh D. Sharma 1 Esra'a Keewan 2 Wojciech Ornatowski 3 Silpita Paul 4 Monique Nysus 5 Christopher C. Barnett 6 Julie Wolfson 7 Quiteria Jacquez 8 Bianca L. Myers 9 Huining Kang 0000-0002-4415-3573 10 Katherine E. Zychowski 11 Stuart S. Winter 0000-0003-3583-7727 12 Mignon L. Loh 13 Stephen P. Hunger 14 Eliseo F. Castillo 0000-0002-5083-560x 15 Tom Taghon 16 Christina Halsey 17 Tou Yia Vue 18 Nick Jones 0000-0003-4846-5117 19 Panagiotis Ntziachristos 20 Ksenia Matlawska-Wasowska 21
title T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
spellingShingle T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
Nick Jones
title_short T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
title_full T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
title_fullStr T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
title_full_unstemmed T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
title_sort T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges
author_id_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
author Nick Jones
author2 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
format Journal article
container_title Journal of Clinical Investigation
container_volume 0
publishDate 2025
institution Swansea University
issn 1558-8238
doi_str_mv 10.1172/jci188888
publisher American Society for Clinical Investigation
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 0
active_str 0
description 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.
published_date 2025-10-23T05:31:38Z
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score 11.089386

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