Cancer Genetics Laboratory, Department of Biochemistry, University of Otago, PO Box 56, Dunedin 9054, New Zealand.
Mol Cancer. 2010 Jun 24;9:163. doi: 10.1186/1476-4598-9-163.
Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome. However, few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. By screening candidate genes, we have detected frequent and dense methylation of the TESTIN (TES) promoter.
Bisulfite sequencing showed that 100% of the ALL samples (n = 20) were methylated at the TES promoter, whereas the matched remission (n = 5), normal bone marrow (n = 6) and normal PBL (n = 5) samples were unmethylated. Expression of TES in hyperdiploid, TEL-AML+, BCR-ABL+, and E2A-PBX+ subtypes of B lineage ALL was markedly reduced compared to that in normal bone marrow progenitor cells and in B cells. In addition TES methylation and silencing was demonstrated in nine out of ten independent B ALL propagated as xenografts in NOD/SCID mice.
In total, 93% of B ALL samples (93 of 100) demonstrated methylation with silencing or reduced expression of the TES gene. Thus, TES is the most frequently methylated and silenced gene yet reported in ALL. TES, a LIM domain-containing tumour suppressor gene and component of the focal adhesion complex, is involved in adhesion, motility, cell-to-cell interactions and cell signalling. Our data implicate TES methylation in ALL and provide additional evidence for the involvement of LIM domain proteins in leukaemogenesis.
在儿童急性淋巴细胞白血病（ALL）中已经报道了异常启动子 DNA 甲基化，并且有可能促成其发病和结果。然而，很少有报道显示与肿瘤特异性基因沉默相关的一致、普遍和密集的启动子甲基化。通过筛选候选基因，我们已经检测到 TESTIN（TES）启动子的频繁和密集甲基化。
亚硫酸氢盐测序显示，100%的 ALL 样本（n=20）在 TES 启动子处甲基化，而匹配的缓解（n=5）、正常骨髓（n=6）和正常 PBL（n=5）样本未甲基化。与正常骨髓祖细胞和 B 细胞相比，TES 在高倍体、TEL-AML+、BCR-ABL+和 E2A-PBX+亚型的 B 谱系 ALL 中的表达明显降低。此外，在作为异种移植物在 NOD/SCID 小鼠中传播的十个独立 B ALL 中的九个中，证实了 TES 甲基化和沉默。
总的来说，93%的 B ALL 样本（100 个中的 93 个）表现出 TES 基因的甲基化和沉默或表达降低。因此，TES 是迄今为止在 ALL 中报道的最频繁甲基化和沉默的基因。TES 是一个 LIM 结构域包含的肿瘤抑制基因，是焦点黏附复合物的组成部分，参与黏附、运动、细胞间相互作用和细胞信号传导。我们的数据提示 TES 甲基化与 ALL 有关，并为 LIM 结构域蛋白参与白血病发生提供了额外的证据。
