Villa-Morales María, Santos Javier, Pérez-Gómez Eduardo, Quintanilla Miguel, Fernández-Piqueras José
Laboratorio de Genética Molecular Humana, Departamento de Biología, Universidad Autónoma de Madrid, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain.
Cancer Res. 2007 Jun 1;67(11):5107-16. doi: 10.1158/0008-5472.CAN-06-4006.
The Fas/FasL system mediates induced apoptosis of immature thymocytes and peripheral T lymphocytes, but little is known about its implication in genetic susceptibility to T-cell malignancies. In this article, we report that the expression of FasL increases early in all mice after gamma-radiation treatments, maintaining such high levels for a long time in mice that resisted tumor induction. However, its expression is practically absent in T-cell lymphoblastic lymphomas. Interestingly, there exist significant differences in the level of expression between two mice strains exhibiting extremely distinct susceptibilities that can be attributed to promoter functional polymorphisms. In addition, several functional nucleotide changes in the coding sequences of both Fas and FasL genes significantly affect their biological activity. These results lead us to propose that germ-line functional polymorphisms affecting either the levels of expression or the biological activity of both Fas and FasL genes could be contributing to the genetic risk to develop T-cell lymphoblastic lymphomas and support the use of radiotherapy as an adequate procedure to choose in the treatment of T-cell malignancies.
Fas/FasL系统介导未成熟胸腺细胞和外周T淋巴细胞的诱导凋亡，但关于其在T细胞恶性肿瘤遗传易感性中的作用知之甚少。在本文中，我们报告FasL的表达在所有接受γ射线照射治疗后的小鼠中早期增加，在抵抗肿瘤诱导的小鼠中长时间维持如此高的水平。然而，在T细胞淋巴母细胞淋巴瘤中其表达几乎不存在。有趣的是，在表现出极其不同易感性的两种小鼠品系之间，表达水平存在显著差异，这可归因于启动子功能多态性。此外，Fas和FasL基因编码序列中的几个功能性核苷酸变化显著影响它们的生物学活性。这些结果使我们提出，影响Fas和FasL基因表达水平或生物学活性的种系功能多态性可能会增加发生T细胞淋巴母细胞淋巴瘤的遗传风险，并支持放疗作为治疗T细胞恶性肿瘤的合适选择。
