Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Age Factors
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Animals
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B-Lymphocyte Subsets / immunology
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B-Lymphocyte Subsets / pathology
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Cells, Cultured
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Chimera
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Cytokines / blood
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DNA, Complementary / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Hypergammaglobulinemia / etiology
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Inflammation / etiology*
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / pathology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / physiology*
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Lymphocyte Activation / immunology*
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Lymphopoiesis / immunology*
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Lymphoproliferative Disorders / etiology*
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Lymphoproliferative Disorders / genetics
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Lymphoproliferative Disorders / immunology
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Lymphoproliferative Disorders / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Phosphorylation
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Positive Regulatory Domain I-Binding Factor 1
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Protein Processing, Post-Translational
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / physiology*
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Recombinant Fusion Proteins
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STAT3 Transcription Factor / metabolism
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Syk Kinase
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology*
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Thymus Gland / immunology
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Thymus Gland / pathology
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transduction, Genetic
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Translocation, Genetic
Substances
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Cytokines
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DNA, Complementary
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Intracellular Signaling Peptides and Proteins
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Oncogene Proteins, Fusion
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Prdm1 protein, mouse
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Transcription Factors
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Positive Regulatory Domain I-Binding Factor 1
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Protein-Tyrosine Kinases
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SYK protein, human
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Syk Kinase
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Syk protein, mouse
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emt protein-tyrosine kinase