| Gene information | Literature | Expression | lncRNA | Mutation | Homolog |
Basic Information | |
|---|---|
Gene ID | 3702 |
Name | ITK |
Synonymous | IL2-inducible T-cell kinase;ITK;IL2-inducible T-cell kinase |
Definition | IL-2-inducible T cell kinase|IL-2-inducible T-cell kinase|T-cell-specific kinase|homolog of mouse T-cell itk/tsk|interleukin-2-inducible T cell kinase|interleukin-2-inducible T-cell kinase|kinase EMT|tyrosine-protein kinase ITK/TSK|tyrosine-protein kinase |
Position | 5q31-q32 |
Gene type | protein-coding |
Title | Abstract |
| The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. | Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in ALL transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8- and CD3+CD4-CD8- ITK-SYK-positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-gamma. ITK-SYK-positive T-cells showed enhanced apoptosis resistance and INF-gamma production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy. |
| Premature terminal differentiation protects from deregulated lymphocyte activation by ITK-Syk. | 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. |