Watt P M, Kumar R, Kees U R
TVW Telethon Institute for Child Health Research and Centre for Child Health Research, University of Western Australia, West Perth, Australia.
Genes Chromosomes Cancer. 2000 Dec;29(4):371-7. doi: 10.1002/1098-2264(2000)9999:9999<::aid-gcc1050>3.0.co;2-y.
Despite considerable work on the epigenetic control of tumor suppressor genes, little is known about the potential role of promoter CpG demethylation in the activation of oncogenes in lymphoid tumors. The HOX11 proto-oncogene is frequently activated in T-cell acute lymphoblastic leukemia (T-ALL). HOX11 activation can occur in the absence of translocation of the gene to the T-cell receptor locus (Salvati et al., 1995), implying that activation mechanisms must be involved other than the juxtaposition of the gene to adjacent enhancing sequences. We tested whether the methylation status of the proximal promoter was correlated with expression status in T-ALL and found that, in all cases, expression of HOX11 in T-ALL was associated with extensive demethylation of the proximal HOX11 promoter, regardless of whether or not translocation was involved. In contrast, cells that did not express HOX11 showed a more methylated pattern of CpG residues in the proximal promoter. Methylation of this sequence in vitro was sufficient to silence the proximal promoter. We propose a model in which the selection of leukemia clones via a pathway involving HOX11 expression requires the demethylation of its promoter as a prerequisite for additional gene activation mechanisms.
尽管在肿瘤抑制基因的表观遗传控制方面已经开展了大量工作，但对于启动子CpG去甲基化在淋巴肿瘤癌基因激活中的潜在作用却知之甚少。HOX11原癌基因在T细胞急性淋巴细胞白血病（T-ALL）中经常被激活。HOX11的激活可以在该基因未易位至T细胞受体基因座的情况下发生（Salvati等人，1995年），这意味着除了基因与相邻增强序列并列之外，必定还涉及其他激活机制。我们测试了T-ALL中近端启动子的甲基化状态是否与表达状态相关，结果发现在所有情况下，T-ALL中HOX11的表达都与近端HOX11启动子的广泛去甲基化有关，无论是否涉及易位。相反，不表达HOX11的细胞在近端启动子中显示出更多的CpG残基甲基化模式。该序列在体外的甲基化足以使近端启动子沉默。我们提出了一个模型，其中通过涉及HOX11表达的途径选择白血病克隆需要其启动子去甲基化，作为其他基因激活机制的先决条件。
