Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk

J Immunol. 2014 Feb 1;192(3):1024-33. doi: 10.4049/jimmunol.1300420. Epub 2013 Dec 27.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / pathology
  • Cells, Cultured
  • Chimera
  • Cytokines / blood
  • DNA, Complementary / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hypergammaglobulinemia / etiology
  • Inflammation / etiology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lymphocyte Activation / immunology*
  • Lymphopoiesis / immunology*
  • Lymphoproliferative Disorders / etiology*
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / immunology
  • Lymphoproliferative Disorders / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / physiology*
  • Phosphorylation
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein Processing, Post-Translational
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / physiology*
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor / metabolism
  • Syk Kinase
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocyte Subsets / pathology*
  • Thymus Gland / immunology
  • Thymus Gland / pathology
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transduction, Genetic
  • Translocation, Genetic

Substances

  • Cytokines
  • DNA, Complementary
  • Intracellular Signaling Peptides and Proteins
  • Oncogene Proteins, Fusion
  • Prdm1 protein, mouse
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Syk protein, mouse
  • emt protein-tyrosine kinase