Premature Terminal Differentiation Protects from Deregulated Lymphocyte Activation by ITK-Syk
Premature Terminal Differentiation Protects from Deregulated Lymphocyte Activation by ITK-Syk
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DOI：
10.4049/jimmunol.1300420
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发表时间：
2014-02-01
影响因子：
4.4
通讯作者：
Jumaa, Hassan
中科院分区：
文献类型：
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作者：
Bach, Martina P.;Hug, Eva;Jumaa, Hassan
造血系统肿瘤的发生通常与突变、基因表达改变或染色体易位有关。最近，在外周 T 细胞淋巴瘤亚群中发现了 t(5, 9)(q33; q22) 易位，并显示其导致 IL-2 诱导激酶-脾酪氨酸激酶 (ITK-Syk) 融合转录本。在这项研究中，我们发现，小鼠中 ITK-Syk 癌基因的 T 细胞特异性表达导致小鼠在 7-9 周龄时出现早期发作和侵袭性多克隆 T 细胞淋巴增殖，并伴随 B 细胞扩张和全身炎症。由于这种表型与之前的研究显着不同，之前的研究表明 ITK-Syk 表达会在 20-27 周龄时引起克隆性 T 细胞淋巴瘤，因此我们更详细地研究了潜在的分子机制。我们发现，严重表型的原因是 ITK-Syk 低表达导致 B 淋巴细胞诱导的成熟蛋白 1 (Blimp-1) 缺乏诱导。相比之下，ITK-Syk癌基因的高表达通过激活Blimp-1诱导胸腺中的终末T细胞分化，从而导致在发育早期消除表达癌基因的细胞。我们的数据表明，终末分化是防止癌基因表达细胞恶性转化的重要机制，因为高 ITK-Syk 癌基因活性会诱导细胞消除。因此，为了转化，需要特定量的癌基因，或者，终末分化的诱导是有缺陷的。
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.