Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma
Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secon...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.1085672/full |
| _version_ | 1797956652462243840 |
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| author | Giulia Mura Elif Karaca Atabay Matteo Menotti Cinzia Martinengo Chiara Ambrogio Chiara Ambrogio Gloria Giacomello Maddalena Arigoni Maddalena Arigoni Martina Olivero Martina Olivero Raffaele A. Calogero Raffaele A. Calogero Roberto Chiarle Roberto Chiarle Claudia Voena |
| author_facet | Giulia Mura Elif Karaca Atabay Matteo Menotti Cinzia Martinengo Chiara Ambrogio Chiara Ambrogio Gloria Giacomello Maddalena Arigoni Maddalena Arigoni Martina Olivero Martina Olivero Raffaele A. Calogero Raffaele A. Calogero Roberto Chiarle Roberto Chiarle Claudia Voena |
| author_sort | Giulia Mura |
| collection | DOAJ |
| description | Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL. |
| first_indexed | 2024-04-10T23:52:13Z |
| format | Article |
| id | doaj.art-317284211cdb4f5b928511d2e4a6a4d4 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-10T23:52:13Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-317284211cdb4f5b928511d2e4a6a4d42023-01-10T15:47:36ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-01-011210.3389/fonc.2022.10856721085672Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphomaGiulia Mura0Elif Karaca Atabay1Matteo Menotti2Cinzia Martinengo3Chiara Ambrogio4Chiara Ambrogio5Gloria Giacomello6Maddalena Arigoni7Maddalena Arigoni8Martina Olivero9Martina Olivero10Raffaele A. Calogero11Raffaele A. Calogero12Roberto Chiarle13Roberto Chiarle14Claudia Voena15Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyDepartment of Pathology, Children’s Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyMolecular Biotechnology Center (MBC), University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyMolecular Biotechnology Center (MBC), University of Torino, Torino, ItalyCandiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, ItalyDepartment of Oncology, University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyMolecular Biotechnology Center (MBC), University of Torino, Torino, ItalyDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyDepartment of Pathology, Children’s Hospital and Harvard Medical School, Boston, MA, United StatesDepartment of Molecular Biotechnology and Health Sciences, University of Torino, Torino, ItalyAnaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL.https://www.frontiersin.org/articles/10.3389/fonc.2022.1085672/fullanaplastic large cell lymphomaALKCD45phosphatasesresistancetyrosine kinase inhibitor |
| spellingShingle | Giulia Mura Elif Karaca Atabay Matteo Menotti Cinzia Martinengo Chiara Ambrogio Chiara Ambrogio Gloria Giacomello Maddalena Arigoni Maddalena Arigoni Martina Olivero Martina Olivero Raffaele A. Calogero Raffaele A. Calogero Roberto Chiarle Roberto Chiarle Claudia Voena Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma Frontiers in Oncology anaplastic large cell lymphoma ALK CD45 phosphatases resistance tyrosine kinase inhibitor |
| title | Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma |
| title_full | Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma |
| title_fullStr | Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma |
| title_full_unstemmed | Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma |
| title_short | Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma |
| title_sort | regulation of cd45 phosphatase by oncogenic alk in anaplastic large cell lymphoma |
| topic | anaplastic large cell lymphoma ALK CD45 phosphatases resistance tyrosine kinase inhibitor |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.1085672/full |
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