| First Author | Bach MP | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 3 | Pages | 1024-33 |
| PubMed ID | 24376268 | Mgi Jnum | J:207306 |
| Mgi Id | MGI:5555989 | Doi | 10.4049/jimmunol.1300420 |
| Citation | Bach MP, et al. (2014) Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk. J Immunol 192(3):1024-33 |
| abstractText | 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. |
