Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk
| Autor: | Katja Zirlik, Markus Werner, Jürgen Ruland, Eva Hug, Christine Dierks, Julian Holch, Robert Zeiser, Martina P. Bach, Hassan Jumaa, Konstanze Pechloff, Clara Sprissler |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
STAT3 Transcription Factor
DNA Complementary Oncogene Proteins Oncogene Proteins Fusion T cell Recombinant Fusion Proteins Immunology Cell B-Lymphocyte Subsets Syk Mice Transgenic Thymus Gland Biology Lymphocyte Activation Translocation Genetic Mice T-Lymphocyte Subsets Transduction Genetic Hypergammaglobulinemia medicine Immunology and Allergy Animals Humans Syk Kinase Phosphorylation B cell Cells Cultured Regulation of gene expression Inflammation Oncogene Chimera Lymphopoiesis Age Factors Intracellular Signaling Peptides and Proteins Protein-Tyrosine Kinases Molecular biology Lymphoproliferative Disorders Gene Expression Regulation Neoplastic Mice Inbred C57BL medicine.anatomical_structure T cell differentiation Cancer research Cytokines Female Positive Regulatory Domain I-Binding Factor 1 Protein Processing Post-Translational Transcription Factors |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 192(3) |
| ISSN: | 1550-6606 |
| Popis: | The development of hematopoietic neoplasms is often associated with mutations, altered gene expression or chromosomal translocations. Recently, the t(5, 9)(q33;q22) translocation was found in a subset of peripheral T cell lymphomas and was shown to result in an IL-2–inducible kinase–spleen tyrosine kinase (ITK-Syk) fusion transcript. In this study, we show that T cell–specific expression of the ITK-Syk oncogene in mice leads to an early onset and aggressive polyclonal T cell lymphoproliferation with concomitant B cell expansion and systemic inflammation by 7–9 wk of age. Because this phenotype is strikingly different from previous work showing that ITK-Syk expression causes clonal T cell lymphoma by 20–27 wk of age, we investigated the underlying molecular mechanism in more detail. We show that the reason for the severe phenotype is the lack of B-lymphocyte–induced maturation protein-1 (Blimp-1) induction by low ITK-Syk expression. In contrast, high ITK-Syk oncogene expression induces terminal T cell differentiation in the thymus by activating Blimp-1, thereby leading to elimination of oncogene-expressing cells early in development. Our data suggest that terminal differentiation is an important mechanism to prevent oncogene-expressing cells from malignant transformation, as high ITK-Syk oncogene activity induces cell elimination. Accordingly, for transformation, a specific amount of oncogene is required, or alternatively, the induction of terminal differentiation is defective. |
| Databáze: | OpenAIRE |
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