Demeter J, Porzsolt F, Rämisch S, Schmidt D, Schmid M, Messer G
Department of Medicine III, University of Ulm, Germany.
Br J Haematol. 1997 Apr;97(1):107-12. doi: 10.1046/j.1365-2141.1997.9912636.x.
The neoplastic cells of CLL are able to produce TNF which is known to stimulate the proliferation of CLL cells in an autocrine and paracrine manner. Genetic polymorphism of molecules of the TNF ligand superfamily has been described and certain alleles were suspected to predispose to variant biological responses. Previously, the rare allele TNFB1 of the TNF-beta/lymphotoxin (LT)-alpha gene (NcoI, asparagine at amino acid position 26) was found to be associated with a stronger LT-alpha response of PBMC in vitro. We now report on a significant increase of the allele TNF1 (TNFA -308 G) of the TNF-alpha promoter/enhancer polymorphism in a group of 73 CLL patients when compared to healthy individuals (RR = 3.18, 95% confidence interval 1.57-8.3; P = 0.006). The allelic distribution of the TNF-beta/LT-alpha NcoI polymorphism did not differ significantly from randomized healthy controls. On the other hand, the frequency of the allele TNFB2 was increased in CLL patients with advanced clinical stage (P = 0.004). These findings indicate immunogenetic associations involving polymorphisms of cytokine genes serving as paracrine and autocrine growth factors, which thus can contribute to the pathogenesis of the TNF/LT-sensitive haematological malignancy CLL.
慢性淋巴细胞白血病（CLL）的肿瘤细胞能够产生肿瘤坏死因子（TNF），已知其以自分泌和旁分泌方式刺激CLL细胞增殖。TNF配体超家族分子的基因多态性已有描述，某些等位基因被怀疑易导致不同的生物学反应。此前，发现TNF-β/淋巴毒素（LT）-α基因（NcoI，氨基酸位置26处为天冬酰胺）的罕见等位基因TNFB1与体外PBMC更强的LT-α反应相关。我们现在报告，与健康个体相比，一组73例CLL患者中TNF-α启动子/增强子多态性的等位基因TNF1（TNFA -308 G）显著增加（相对风险=3.18，95%置信区间1.57 - 8.3；P = 0.006）。TNF-β/LT-α NcoI多态性的等位基因分布与随机选择的健康对照无显著差异。另一方面，临床分期较晚的CLL患者中，等位基因TNFB2的频率增加（P = 0.004）。这些发现表明免疫遗传学关联涉及作为旁分泌和自分泌生长因子的细胞因子基因多态性，因此可能在TNF/LT敏感的血液系统恶性肿瘤CLL的发病机制中起作用。
