Frequent silencing of fragile histidine triad gene (FHIT) in Burkitt's lymphoma is associated with aberrant hypermethylation
Frequent silencing of fragile histidine triad gene (FHIT) in Burkitt's lymphoma is associated with aberrant hypermethylation
复制标题
DOI：
10.1002/gcc.20099
复制
发表时间：
2004-12-01
影响因子：
3.7
通讯作者：
Bhatia, K
中科院分区：
文献类型：
--
作者：
Hussain, A;Gutiérrez, MI;Bhatia, K
脆性组氨酸三联体（FHIT）基因是一种潜在的肿瘤抑制基因，在多种人类癌症中经常失活。然而，FHIT基因在伯基特淋巴瘤（BL）中仍然很大程度上未被探索。因此，我们评估是否FHIT表达的损失发生在BL，如果是这样，这种损失的机制是什么。在50%的BL细胞系中观察到蛋白表达缺乏。甲基化特异性聚合酶链反应（MSP）显示45%的BL细胞系携带异常甲基化的FHIT等位基因。亚硫酸氢盐处理的DNA测序证实了这些数据，并表明在所有甲基化等位基因中甲基化的密度非常高。实时定量逆转录PCR分析表明，全长FHIT转录的衰减与甲基化相关。转录本测序结果表明，异常转录导致FHIT外显子的丢失更常见于BL含有未甲基化的FHIT基因。然而，这样的成绩单往往与全长FHIT成绩单共存。因此，BL中FHIT蛋白的丢失与CpG岛甲基化相关，而不是与异常转录相关，这并不奇怪。FHIT甲基化也在31%（16/51）的原发性BL中检测到，包括2个衍生细胞系也表现出FHIT高甲基化的样本。因此，异常甲基化可以在体内发生。总之，本报告提供的证据表明，表观遗传修饰经常导致BL中FHIT表达的丧失。(C)2004 Wiley-Liss，Inc.
The fragile histidine triad (FHIT) gene, a potential tumor-suppressor gene, is frequently inactivated in multiple human cancers. However, the FHIT gene remains largely unexplored in Burkitt's lymphoma (BL). Hence, we assessed whether loss of FHIT expression occurs in BL, and, if so, what is the mechanism of such loss. Lack of protein expression was observed in 50% of BL cell lines. Methylation-specific polymerase chain reaction (MSP) showed that 45% of BL cell lines carried aberrantly methylated FHIT alleles. Sequencing of bisulfite-treated DNA confirmed these data and indicated a very high density of methylation in all methylated alleles. Real-time, quantitative reverse-transcription PCR analysis indicated that attenuation of full-length FHIT transcription was correlated with methylation. Sequencing of transcripts illustrated that aberrant transcription resulting in loss of FHIT exons occurred more commonly in BL containing unmethylated FHIT genes. However, such transcripts often coexisted with full-length FHIT transcripts. Not surprisingly, therefore, loss of FHIT protein in BL correlated with CpG island methylation, rather than with aberrant transcription. FHIT methylation also was detected in 31% (16 of 5 1) of the primary BLs examined, including 2 samples whose derived cell lines also manifested FHIT hypermethylation. Aberrant methylation can thus occur in vivo. In summary, this report provides evidence that epigenetic modification frequently results in loss of FHIT expression in BL. (C) 2004 Wiley-Liss, Inc.