title: Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk.
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.
authors.affiliation: Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany;
authors.forename: Martina P
authors.initials: MP
authors.lastname: Bach
authors.forename: Eva
authors.initials: E
authors.lastname: Hug
authors.forename: Markus
authors.initials: M
authors.lastname: Werner
authors.forename: Julian
authors.initials: J
authors.lastname: Holch
authors.forename: Clara
authors.initials: C
authors.lastname: Sprissler
authors.forename: Konstanze
authors.initials: K
authors.lastname: Pechloff
authors.forename: Katja
authors.initials: K
authors.lastname: Zirlik
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.forename: Christine
authors.initials: C
authors.lastname: Dierks
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
mesh_terms: D000367:Age Factors; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002678:Chimera; D016207:Cytokines / Q000097:blood; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006942:Hypergammaglobulinemia / Q000209:etiology; D007249:Inflammation / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D038041:Lymphopoiesis / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000072377:Syk Kinase; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D014178:Translocation, Genetic
chemical_list: D016207:Cytokines; D018076:DNA, Complementary; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C513258:Prdm1 protein, mouse; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C080813:emt protein-tyrosine kinase