Journal article 271 views 2 downloads
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, Volume: 136, Issue: 2, Start page: e188888
Swansea University Author:
Nick Jones
-
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© 2025, Sharma et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
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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...
| Published in: | Journal of Clinical Investigation |
|---|---|
| ISSN: | 0021-9738 1558-8238 |
| Published: |
American Society for Clinical Investigation
2026
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa70767 |
| first_indexed |
2025-10-24T15:13:07Z |
|---|---|
| last_indexed |
2026-02-25T05:36:12Z |
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cronfa70767 |
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<?xml version="1.0"?><rfc1807><datestamp>2026-02-24T11:31:15.9310587</datestamp><bib-version>v2</bib-version><id>70767</id><entry>2025-10-24</entry><title>T-cell acute lymphoblastic leukemia exploits a neural proinflammatory pathway to colonize the meninges</title><swanseaauthors><author><sid>0fce0f7ddbdbfeb968f4e2f1e3f86744</sid><ORCID>0000-0003-4846-5117</ORCID><firstname>Nick</firstname><surname>Jones</surname><name>Nick Jones</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2025-10-24</date><deptcode>MEDS</deptcode><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.</abstract><type>Journal Article</type><journal>Journal of Clinical Investigation</journal><volume>136</volume><journalNumber>2</journalNumber><paginationStart>e188888</paginationStart><paginationEnd/><publisher>American Society for Clinical Investigation</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>0021-9738</issnPrint><issnElectronic>1558-8238</issnElectronic><keywords/><publishedDay>16</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2026</publishedYear><publishedDate>2026-01-16</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>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.
• The National Cancer Institute (NCI) grant R01 CA237165 and R01 CA282701 (to KMW).
• O’Neal Invest (to KMW).
• Children’s Oncology Group Specimen Banking (U24 CA114766), (AALL15B1-Q, to KMW).
• NCI Cancer Center Support Grant P30 CA013148 (UAB) and P30 CA118100 (UNM).
• Dixon Foundation (to CCB).
• Research Foundation Flanders Ghent University and Flanders interuniversity consortium grant (to PN).
• Cancer Research Institute Ghent (CRIG) partnership grant (FWO G0F4721N and BOF.IBO.2023.0006.02, to PN).
• 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).
• Cancer Research UK Programme Foundation Award (DRCPFA-Nov21\100001, to CH).
• American Cancer Society Research Scholar (to KMW).</funders><projectreference/><lastEdited>2026-02-24T11:31:15.9310587</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><document><filename>70767__36296__fe00d152d2334e45ac3e55a0924bb787.pdf</filename><originalFilename>70767.VOR.pdf</originalFilename><uploaded>2026-02-24T11:28:30.5296514</uploaded><type>Output</type><contentLength>11422583</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2025, Sharma et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>https://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807> |
| spelling |
2026-02-24T11:31:15.9310587 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 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 Article Journal of Clinical Investigation 136 2 e188888 American Society for Clinical Investigation 0021-9738 1558-8238 16 1 2026 2026-01-16 10.1172/jci188888 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee 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. • The National Cancer Institute (NCI) grant R01 CA237165 and R01 CA282701 (to KMW). • O’Neal Invest (to KMW). • Children’s Oncology Group Specimen Banking (U24 CA114766), (AALL15B1-Q, to KMW). • NCI Cancer Center Support Grant P30 CA013148 (UAB) and P30 CA118100 (UNM). • Dixon Foundation (to CCB). • Research Foundation Flanders Ghent University and Flanders interuniversity consortium grant (to PN). • Cancer Research Institute Ghent (CRIG) partnership grant (FWO G0F4721N and BOF.IBO.2023.0006.02, to PN). • 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). • Cancer Research UK Programme Foundation Award (DRCPFA-Nov21\100001, to CH). • American Cancer Society Research Scholar (to KMW). 2026-02-24T11:31:15.9310587 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 70767__36296__fe00d152d2334e45ac3e55a0924bb787.pdf 70767.VOR.pdf 2026-02-24T11:28:30.5296514 Output 11422583 application/pdf Version of Record true © 2025, Sharma et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License. true eng https://creativecommons.org/licenses/by/4.0/ |
| 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 |
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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 |
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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 |
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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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2026-01-16T05:28:03Z |
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