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The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma

Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T...

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Autores principales: Pechloff, Konstanze, Holch, Julian, Ferch, Uta, Schweneker, Marc, Brunner, Kristina, Kremer, Markus, Sparwasser, Tim, Quintanilla-Martinez, Leticia, Zimber-Strobl, Ursula, Streubel, Berthold, Gewies, Andreas, Peschel, Christian, Ruland, Jürgen
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867290/
https://www.ncbi.nlm.nih.gov/pubmed/20439541
http://dx.doi.org/10.1084/jem.20092042
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author Pechloff, Konstanze
Holch, Julian
Ferch, Uta
Schweneker, Marc
Brunner, Kristina
Kremer, Markus
Sparwasser, Tim
Quintanilla-Martinez, Leticia
Zimber-Strobl, Ursula
Streubel, Berthold
Gewies, Andreas
Peschel, Christian
Ruland, Jürgen
author_facet Pechloff, Konstanze
Holch, Julian
Ferch, Uta
Schweneker, Marc
Brunner, Kristina
Kremer, Markus
Sparwasser, Tim
Quintanilla-Martinez, Leticia
Zimber-Strobl, Ursula
Streubel, Berthold
Gewies, Andreas
Peschel, Christian
Ruland, Jürgen
author_sort Pechloff, Konstanze
collection PubMed
description Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.
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spelling pubmed-28672902010-11-10 The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma Pechloff, Konstanze Holch, Julian Ferch, Uta Schweneker, Marc Brunner, Kristina Kremer, Markus Sparwasser, Tim Quintanilla-Martinez, Leticia Zimber-Strobl, Ursula Streubel, Berthold Gewies, Andreas Peschel, Christian Ruland, Jürgen J Exp Med Article Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL. The Rockefeller University Press 2010-05-10 /pmc/articles/PMC2867290/ /pubmed/20439541 http://dx.doi.org/10.1084/jem.20092042 Text en © 2010 Pechloff et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Article
Pechloff, Konstanze
Holch, Julian
Ferch, Uta
Schweneker, Marc
Brunner, Kristina
Kremer, Markus
Sparwasser, Tim
Quintanilla-Martinez, Leticia
Zimber-Strobl, Ursula
Streubel, Berthold
Gewies, Andreas
Peschel, Christian
Ruland, Jürgen
The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title_full The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title_fullStr The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title_full_unstemmed The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title_short The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma
title_sort fusion kinase itk-syk mimics a t cell receptor signal and drives oncogenesis in conditional mouse models of peripheral t cell lymphoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867290/
https://www.ncbi.nlm.nih.gov/pubmed/20439541
http://dx.doi.org/10.1084/jem.20092042
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