Sustained NF-kappaB activity in chronic lymphocytic leukemia is independent of genetic and epigenetic alterations in the TNFAIP3 (A20) locus
Sustained NF-kappaB activity in chronic lymphocytic leukemia is independent of genetic and epigenetic alterations in the TNFAIP3 (A20) locus
复制标题
DOI：
10.1002/ijc.25579
复制
发表时间：
2011-05-01
影响因子：
6.4
通讯作者：
Wendtner, Clemens-Martin
中科院分区：
文献类型：
--
作者：
Frenzel, Lukas P.;Claus, Rainer;Wendtner, Clemens-Martin
不适当的核因子（NF）κ B活性是B细胞恶性肿瘤和慢性淋巴细胞白血病（CLL）的一个主要标志。NF κ B依赖性基因参与抗凋亡、细胞增殖和转移，并负责肿瘤的存活和增殖。然而，NF κ B B活性在CLL中的作用机制仍有待阐明。以前，我们在染色体6 q上编码肿瘤坏死因子α诱导蛋白3的区域中鉴定了易位，该蛋白3是NF κ B负反馈环调节的关键参与者。这种泛素编辑酶的失活涉及免疫病理学和肿瘤发生。A20位点的频繁突变导致持续的NF κ B B活性，可能在不同B细胞恶性肿瘤的发生中起主导作用。为了检查A20是否参与CLL中NF kappa B活性的上调，我们对55份CLL DNA样本中A20基因的外显子2-9进行了测序。此外，我们确定了63个CLL DNA样品中启动子区域的甲基化状态，并与来自健康供体的B细胞的10个对照DNA进行比较。与其他B细胞恶性肿瘤的报道相反，A20区域既没有突变也没有异常的DNA甲基化。此外，其表达可以通过免疫印迹证实，并显示与健康B细胞相当的结果。这些结果表明，CLL的恶性发展与大多数其他B细胞恶性肿瘤不同，后者显示A20的频繁失活。
Inappropriate nuclear factor (NF) kappa B activity is one major hallmark of B-cell malignancies and chronic lymphocytic leukemia (CLL). NF kappa B-dependent genes are involved in antiapoptosis, cell proliferation and metastasis and are responsible for survival and proliferation of tumors. However, the mechanisms of NF kappa B activity in CLL still need to be elucidated. Previously, we identified translocations in a region on chromosome 6q that encodes tumor necrosis factor alpha-induced protein 3, which is a key player in negative feedback loop regulation of NF kappa B. Inactivation of this ubiquitin-editing enzyme is involved in immunopathologies and in tumorigenesis. Frequent mutations in the A20 locus-leading to sustained NF kappa B activity-could be shown to play a dominant role in development of different B-cell malignancies. To check if A20 is involved in upregulation of NF kappa B activity in CLL, we sequenced Exons 2-9 of the A20 gene in 55 CLL DNA samples. Furthermore, we determined the methylation status of the promoter region in 63 CLL DNA samples and compared to 10 control DNAs of B cells from healthy donors. Contrary to reports from other B-cell malignancies, the A20 region showed neither mutations nor aberrant DNA methylation. Moreover, its expression could be confirmed by immunoblotting and showing comparable results to healthy B cells. These results indicate that malignant development in CLL differs from most of other B-cell malignancies, which show frequent inactivation of A20.