The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma.
The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma.
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DOI：
10.1084/jem.20092042
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发表时间：
2010-05-10
期刊：
影响因子：
--
通讯作者：
Ruland J
中科院分区：
文献类型：
--
作者：
Pechloff K;Holch J;Ferch U;Schweneker M;Brunner K;Kremer M;Sparwasser T;Quintanilla-Martinez L;Zimber-Strobl U;Streubel B;Gewies A;Peschel C;Ruland J
外周T细胞淋巴瘤(PTCL)是一种高度侵袭性的恶性肿瘤，预后差。它们的分子发病机制尚不清楚，也缺乏针对该疾病的小动物模型。最近，染色体易位t(5；9)(q33；q22)产生白细胞介素2(IL-2)诱导的T细胞激酶(ITK)-脾酪氨酸激酶(SYK)融合酪氨酸激酶被认为是PTCL的复发事件。我们发现ITK-SYK与T细胞中的脂筏结合在一起，并触发T细胞受体(TCR)近端蛋白的抗原非依赖性磷酸化。这些事件导致下游通路的激活和与常规TCR结扎相对应的急性细胞结果，包括CD69的上调或体外IL-2的产生，或胸腺细胞的缺失和体内外周T细胞的激活。最终，患者来源的ITK-SYK在小鼠体内的条件表达诱导出高度恶性的PTCL，其外显率为100%，类似于人类疾病。我们的工作表明，从原理上讲，构成强制的抗原受体信号可以作为一个强大的致癌驱动因素。此外，我们还建立了一个稳健的、临床相关的、可遗传处理的人PTCL模型。
Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)–inducible T cell kinase (ITK)–spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)–proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.
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影响因子：
20.3
作者：
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