Epigenetic inactivation of the miR-34a in hematological malignancies
Epigenetic inactivation of the miR-34a in hematological malignancies
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DOI：
10.1093/carcin/bgq033
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发表时间：
2010-04-01
期刊：
影响因子：
4.7
通讯作者：
Liang, R.
中科院分区：
文献类型：
--
作者：
Chim, C. S.;Wong, K. Y.;Liang, R.
miR-34a是p53的转录靶点，与癌变有关。我们研究了miR-34a甲基化在一系列血液系统恶性肿瘤中的作用，包括急性白血病[急性髓性白血病（AML）和急性淋巴细胞白血病（ALL）]、慢性白血病[慢性淋巴细胞白血病（CLL）和慢性髓性白血病（CML）]、多发性骨髓瘤（MM）和非霍奇金淋巴瘤（NHL）。通过甲基化特异性聚合酶链反应，在12个细胞系和188个诊断样本中研究了miR-34a启动子的甲基化状态。miR-34a启动子在正常对照中未甲基化，但在75%的淋巴瘤和37%的骨髓瘤细胞系中甲基化。低甲基化处理导致miR-34a纯合子甲基化淋巴瘤细胞中pri-miR-34a转录物的重新表达。在诊断时的原始样本中，诊断时4%的CLL、5.5%的MM和18.8%的NHL样本中检测到miR-34a甲基化，但ALL、AML和CML中均未检测到miR-34a甲基化（P = 0.011）。在配对样本的MM患者中，miR-34a甲基化状态在进展过程中保持不变。在淋巴细胞恶性肿瘤中，miR-34a在NHL中优先甲基化（P = 0.018），特别是自然杀伤细胞(NK)/ t细胞淋巴瘤。总之，在血液系统恶性肿瘤中，miR-34a甲基化在NHL，特别是NK/ t细胞淋巴瘤中以肿瘤特异性的方式优先发生高甲基化，因此miR-34a在淋巴瘤发生中的作用值得进一步研究。
miR-34a is a transcriptional target of p53 and implicated in carcinogenesis. We studied the role of miR-34a methylation in a panel of hematological malignancies including acute leukemia [acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL)], chronic leukemia [chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML)], multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). The methylation status of miR-34a promoter was studied in 12 cell lines and 188 diagnostic samples by methylation-specific polymerase chain reaction. miR-34a promoter was unmethylated in normal controls but methylated in 75% lymphoma and 37% myeloma cell lines. Hypomethylating treatment led to re-expression of pri-miR-34a transcript in lymphoma cells with homozygous miR-34a methylation. In primary samples at diagnosis, miR-34a methylation was detected in 4% CLL, 5.5% MM samples and 18.8% of NHL at diagnosis but none of ALL, AML and CML (P = 0.011). In MM patients with paired samples, miR-34a methylation status remained unchanged at progression. Amongst lymphoid malignancies, miR-34a was preferentially methylated in NHL (P = 0.018), in particular natural killer (NK)/T-cell lymphoma. In conclusion, amongst hematological malignancies, miR-34a methylation is preferentially hypermethylated in NHL, in particular NK/T-cell lymphoma, in a tumor-specific manner, therefore the role of miR-34a in lymphomagenesis warrants further study.