Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells.
Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-gamma in haematopoietic tumour cells.
复制标题
通过DNA甲基化和组蛋白脱乙酰化对II类反式激活剂的失活与干扰素 - 伽马在造血性肿瘤细胞中缺乏HLA-DR诱导相关。
DOI：
10.1038/sj.bjc.6601602
复制
发表时间：
2004-02-23
影响因子：
8.8
通讯作者：
Imai, K
中科院分区：
文献类型：
--
作者：
Morimoto, Y;Toyota, M;Satoh, A;Murai, M;Mita, H;Suzuki, H;Takamura, Y;Ikeda, H;Ishida, T;Sato, N;Tokino, T;Imai, K
主要组织相容性复合体（MHC） II类分子通过在细胞表面呈现免疫原性肽，在控制适应性免疫应答中发挥关键作用。无论是组成型表达还是由干扰素-γ诱导表达，MHC II类分子的表达都通过辅助激活因子II类反激活因子（CIITA）进行调节；此外，抑制它们的表达是癌细胞逃避宿主免疫的一种机制。在这项研究中，我们调查了一种MHC II类抗原HLA-DR及其共激活因子在一组造血细胞系中的表达关系，并探讨了异常DNA甲基化在沉默HLA-DR表达中的作用。在研究的26个细胞系中，8个t细胞和2个髓系白血病细胞系的HLA-DR表达缺失，这种缺失与CIITA-PIV表达的抑制密切相关。值得注意的是，失去CIITA-PIV表达的10个细胞系中有9个显示该基因的5 ' CpG岛甲基化。因此，DNA甲基化被认为通过沉默其协同激活因子CIITA-PIV来抑制造血肿瘤细胞中MHC II类分子的表达。此外，在32例原发性急性髓性白血病标本中，有7例检测到CIITA-PIV的甲基化，这表明表观遗传改变不是细胞系特异性现象。总的来说，这些数据表明，通过抑制MHC II类分子的表达，CIITA的表观遗传失活为一部分造血肿瘤提供了生存优势。
By presenting immunogenic peptides at the cell surface, major histocompatibility complex (MHC) class II molecules play a key role in the control of adaptive immune responses. Whether expressed constitutively or induced by interferon-γ, expression of MHC class II molecules is regulated via coactivator class II transactivator (CIITA); moreover, suppression of their expression is one mechanism by which cancer cells escape host immunity. In this study, we surveyed the relationship between the expression of one MHC class II antigen, HLA–DR, and its coactivators in a group of haematopoietic cell lines, and explored the role of the aberrant DNA methylation in silencing HLA-DR expression. Among 26 cell lines studied, HLA-DR expression was lost from eight T-cell and two myeloid leukaemia cell lines, and this loss was closely associated with suppression of CIITA-PIV expression. Notably, nine of the 10 cell lines that lost CIITA-PIV expression showed methylation of the gene's 5′ CpG island. Thus, DNA methylation is believed to inhibit the expression of MHC class II molecules in haematopoietic tumour cells by silencing its coactivator, CIITA-PIV. Furthermore, methylation of CIITA-PIV was detected in seven of 32 primary acute myeloid leukaemia specimens, indicating that epigenetic alteration is not a cell line-specific phenomenon. Collectively, these data suggest that, by suppressing expression of MHC class II molecules, epigenetic inactivation of CIITA provides a survival advantage to a subset of haematopoietic tumours.