T cell functions and organ infiltration by leukemic T cells require cortactin
© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com..
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties, and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to T cell receptor engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to T cell receptor and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system, suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses.
| Errataetall: |
ErratumIn: J Leukoc Biol. 2023 Oct 26;114(5):513. - PMID 37703329 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:113 |
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| Enthalten in: |
Journal of leukocyte biology - 113(2023), 3 vom: 01. März, Seite 315-325 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Castellanos-Martínez, Ramón [VerfasserIn] |
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| Links: |
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| Themen: |
Arp2/3 |
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| Anmerkungen: |
Date Completed 03.03.2023 Date Revised 13.09.2023 published: Print ErratumIn: J Leukoc Biol. 2023 Oct 26;114(5):513. - PMID 37703329 Citation Status MEDLINE |
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| doi: |
10.1093/jleuko/qiad001 |
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NLM353148563 |
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| 100 | 1 | |a Castellanos-Martínez, Ramón |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a T cell functions and organ infiltration by leukemic T cells require cortactin |
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| 500 | |a ErratumIn: J Leukoc Biol. 2023 Oct 26;114(5):513. - PMID 37703329 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © The Author(s) 2023. Published by Oxford University Press on behalf of Society for Leukocyte Biology. All rights reserved. For permissions, please e-mail: journals.permissionsoup.com. | ||
| 520 | |a T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is still fatal in many cases. T cell blasts are characterized by hyperactivation and strong proliferative and migratory capacities. The chemokine receptor CXCR4 is involved in mediating malignant T cell properties, and cortactin has been shown to control CXCR4 surface localization in T-ALL cells. We have previously shown that cortactin overexpression is correlated with organ infiltration and relapse in B-ALL. However, the role of cortactin in T cell biology and T-ALL remains elusive. Here, we analyzed the functional relevance of cortactin for T cell activation and migration and the implications for T-ALL development. We found that cortactin is upregulated in response to T cell receptor engagement and recruited to the immune synapse in normal T cells. Loss of cortactin caused reduced IL-2 production and proliferation. Cortactin-depleted T cells showed defects in immune synapse formation and migrated less due to impaired actin polymerization in response to T cell receptor and CXCR4 stimulation. Leukemic T cells expressed much higher levels of cortactin compared to normal T cells that correlated with greater migratory capacity. Xenotransplantation assays in NSG mice revealed that cortactin-depleted human leukemic T cells colonized the bone marrow significantly less and failed to infiltrate the central nervous system, suggesting that cortactin overexpression drives organ infiltration, which is a major complication of T-ALL relapse. Thus, cortactin could serve as a potential therapeutic target for T-ALL and other pathologies involving aberrant T cell responses | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Arp2/3 | |
| 650 | 4 | |a HS1 | |
| 650 | 4 | |a T cell activation | |
| 650 | 4 | |a T-ALL | |
| 650 | 4 | |a cortactin | |
| 650 | 4 | |a immunological synapse | |
| 650 | 4 | |a migration | |
| 650 | 7 | |a Cortactin |2 NLM | |
| 700 | 1 | |a León-Vega, Iliana I |e verfasserin |4 aut | |
| 700 | 1 | |a Guerrero-Fonseca, Idaira M |e verfasserin |4 aut | |
| 700 | 1 | |a Vargas-Robles, Hilda |e verfasserin |4 aut | |
| 700 | 1 | |a Jiménez-Camacho, Karina E |e verfasserin |4 aut | |
| 700 | 1 | |a Hernández-Galicia, Gabriela |e verfasserin |4 aut | |
| 700 | 1 | |a Ortiz-Navarrete, Vianney F |e verfasserin |4 aut | |
| 700 | 1 | |a Rottner, Klemens |e verfasserin |4 aut | |
| 700 | 1 | |a Medina-Contreras, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Schnoor, Michael |e verfasserin |4 aut | |
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