Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia (Retracted article. See vol. 32, pg. 804, 2013)
Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia (Retracted article. See vol. 32, pg. 804, 2013)
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DOI：
10.1038/sj.onc.1208866
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发表时间：
2005-11-03
期刊：
影响因子：
8
通讯作者：
Torres, A
中科院分区：
文献类型：
--
作者：
Roman-Gomez, J;Jimenez-Velasco, A;Torres, A
异常的全基因组低甲基化被认为通过促进基因组不稳定性与肿瘤发生有关。由于DNA甲基化被认为是逆转录因子沉默的重要机制，人类肿瘤中的低甲基化可能导致逆转录因子重新激活。然而，DNA 低甲基化在慢性粒细胞白血病 (CML) 中的作用仍有待阐明。在本研究中，分析了慢性期（CP，n = 140）和急变期（BC，n = 47）的 CML 样本中 LINE-1 (L1) 逆转录转座子启动子的甲基化状态。 L1 低甲基化在 BC 中 (74.5%) 明显高于 CP (38%) (P < 0.0001)。此外，L1 低甲基化导致 ORF1 有义转录 (P < 0.0001) 和 c-MET 基因反义转录 (P < 0.0001) 的激活，并且与高水平的 BCR-ABL (P = 0.02) 和 DNMT3b4 (P = 0.001) 转录物显着相关。有趣的是，在 CP-CML 中，广泛的 L1 低甲基化与干扰素 (P = 0.004) 或伊马替尼 (P = 0.034) 的细胞遗传学反应和无进展生存期 (P = 0.005) 的不良预后相关。上述结果强烈表明，L1 元件异常启动子低甲基化激活有义和反义转录在 CML 的进展和临床行为中发挥作用。
Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencing of retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronic-phase (CP, n = 140) and the blast crisis (BC, n = 47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (P < 0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (P < 0.0001) and c-MET gene antisense transcription (P < 0.0001), and was significantly associated with high levels of BCR-ABL (P = 0.02) and DNMT3b4 (P = 0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P = 0.004) or imatinib (P = 0.034) and progression-free survival (P = 0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML.