Identification of aberrantly methylated DNA genes in hematological malignancies : its application to cancer diagnosis

血液恶性肿瘤中异常甲基化DNA基因的鉴定：其在癌症诊断中的应用

基本信息

批准号：
14370301
负责人：
MATSUOKA Masao
金额：
$ 8.83万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Epigenetic changes including DNA methylation play an important role in oncogenesis in addition to genetic changes and chromosomal translocations. To clarify the changed pattern of DNA methylation in hematological malignancies, we isolated aberrantly methylated DNA regions by Methylated CpG island amplification/representative difference assay (MCA/RDA).In ATL cells, MEL1S gene was identified as hypomethylated one in ATL cells. Aberrant expression of MEL1S gene was observed in ATL cells, which enables ATL cells resistant to TGF-β. Therefore, MEL1S expression is considered to be one of mechanisms to confer the resistance to TGF-β. On the other hand, many genes were found to be hypermethylated in ATL cells. Among them, KLF4 and EGR3 genes were studied in ATL cells. EGR3 gene is a transcriptional factor, which is critical for Fas ligand gene transcription. Although ATL cells highly express Fas antigen, they escape from apoptosis due to loss of Fas ligand expression. Silenced EGR3 gene expression in ATL cells is considered to result in loss of Fas ligand expression, which enables ATL cells to escape from Fas-Fas ligand induced apoptosis.With MCA/RDA, we also identified hyper and hypomethylated DNA regions in B-cell chronic lymphocytic leukemia (B-CLL) compared with normal CD19 positive B-cells. We isolated 5 hyper and 27 hypomethylated DNA regions in genomic DNA from B-CLL patient. Hypomethylated DNA regions clustered in chr. 9q34,10q25-26, and 19q13.These aberrantly methylated genes should be implicated in oncogenesis of these hematological malignancies, and detection of these methylation can be used for diagnosis and estimation of the prognosis.

除了遗传变化和染色体易位之外，包括 DNA 甲基化在内的表观遗传变化在肿瘤发生中也发挥着重要作用。为了阐明血液恶性肿瘤中 DNA 甲基化的变化模式，我们通过甲基化 CpG 岛扩增/代表性差异分析 (MCA/) 分离了异常甲基化的 DNA 区域。 RDA）。在ATL细胞中，MEL1S基因被鉴定为低甲基化基因，在ATL细胞中MEL1S基因表达异常。因此，MEL1S 表达被认为是赋予 ATL 细胞抗性的机制之一。另一方面，发现许多基因在 ATL 细胞中高度甲基化。其中，在ATL细胞中研究的KLF4和EGR3基因是一种转录因子，对于Fas配体转录基因至关重要，尽管ATL细胞高表达Fas抗原，但由于Fas抗原的缺失而逃避了细胞凋亡。 Fas配体表达被认为是ATL细胞中EGR3基因表达的缺失，从而使ATL细胞能够逃避Fas-Fas配体诱导的细胞凋亡。通过MCA/RDA，我们还鉴定了ATL细胞中高甲基化和低甲基化的DNA区域。 B 细胞慢性淋巴细胞白血病 (B-CLL) 与正常 CD19 阳性 B 细胞相比，我们从 B-CLL 患者的基因组 DNA 中分离出 5 个高甲基化 DNA 区域和 27 个低甲基化 DNA 区域。低甲基化的DNA区域聚集在9q34、10q25-26和19q13。这些异常甲基化的基因应该与这些血液恶性肿瘤的发生有关，并且检测这些甲基化可用于诊断和估计预后。