AI Article Synopsis

  • - Peripheral T cell lymphomas (PTCLs) are aggressive cancers with poor outcomes, and their underlying biology is not fully understood, particularly due to a lack of small animal models for research.
  • - A specific chromosomal translocation t(5;9) was discovered, creating a fusion protein (ITK-SYK) that continuously activates T cell signaling pathways, mimicking natural T cell receptor activation without the need for antigens.
  • - Mice engineered to express the ITK-SYK fusion protein develop highly malignant PTCLs that closely resemble the human condition, highlighting the role of unchecked T cell signaling in cancer progression and providing a valuable model for future studies.

Article Abstract

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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2867290PMC
http://dx.doi.org/10.1084/jem.20092042DOI Listing

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