ITK-Syk from Deregulated Lymphocyte Activation by Premature Terminal Differentiation Protects

The development of hematopoietic neoplasms is often associated with mutations, altered gene expression or chromosomal trans-locations. 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. S pleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase that possesses two N-terminal Src homology 2 domains and a C-terminal kinase domain. Syk is widely expressed in all hematopoietic cells, mediates various biological functions, and plays a central role in B cell development and signal transduction downstream of the BCR (1–4). In T cells, Syk is mainly expressed at the double-negative and double-positive (DP) developmental stages, but its expression is markedly reduced in later stages of T cell development (5, 6). Deregulated Syk expression or activity has been frequently linked to distinct hematological and non-hematological malignancies and seems to play an important role in the development and maintenance of B cell lineage neoplasms. For instance, inhibition of Syk induces apoptosis of chronic lym-phocytic leukemia and diffuse large B cell lymphoma cells, indicating that Syk is crucial for the survival of these cells (7, 8). Syk has also been linked to malignancies of other hematopoietic lineages such as peripheral T cell lymphomas (PTCLs), in which Syk is overexpressed in .90% of all PTCLs (9). The gene encoding Syk has also been shown to be affected by chromosomal translocations. Chromosomal translocations are …