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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370301/
• 关键词: DNA methylation; CLL; ATL; Epigenetics; tumor suppresson gene; サイレンシング; エピジェネティック; 発がん; 成人T細胞白血病; 血液腫瘍

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.

表观遗传学改变，包括DNA甲基化，除了遗传改变和染色体易位外，在肿瘤发生中也起着重要作用。为了阐明血液系统恶性肿瘤中DNA甲基化的改变模式，我们通过甲基化CpG岛扩增/代表性差异分析(MCA/RDA)分离了异常甲基化的DNA区域。在ATL细胞中，MEL1S基因被鉴定为ATL细胞的低甲基化基因。在ATL细胞中观察到MEL1S基因的异常表达，从而使ATL细胞对转化生长因子-β产生抵抗。因此，MEL1s的表达被认为是肿瘤对转化生长因子-β产生抵抗的机制之一。另一方面，在ATL细胞中发现许多基因高甲基化。其中，KLF4和EGR3基因在ATL细胞中得到了研究。EGR3基因是一种转录因子，对Fas配体基因的转录起关键作用。虽然ATL细胞高度表达Fas抗原，但由于Fas配体的表达缺失，ATL细胞可逃脱凋亡。沉默的EGR3基因在ATL细胞中的表达被认为是导致Fas配体表达缺失，从而使ATL细胞逃脱Fas-Fas配体诱导的凋亡。我们从B-CLL患者基因组DNA中分离到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CHR中。9q34、10q25-26和19q13这些基因的异常甲基化可能与这些血液系统恶性肿瘤的发生有关，检测这些甲基化可用于诊断和估计预后。

项目成果

Otaka A: "Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells"Angew.Chem.Int.Ed.. 41. 2937-2940 (2002)

Otaka A：“gp41-C34 肽的重塑导致 HIV-1 与靶细胞融合的高效抑制剂”Angew.Chem.Int.Ed.. 41. 2937-2940 (2002)

Matsuoka M: "Human T-cell leukemia virus type I and adult T-cell leukemia"Oncogene. 22. 5131-5140 (2003)

松冈M：“人类T细胞白血病病毒I型和成人T细胞白血病”癌基因。

Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro

• DOI: 10.1038/sj.leu.2403400
• 发表时间: 2004-08-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Satou, Y;Nosaka, K;Matsuoka, M
• 通讯作者: Matsuoka, M

Tobinai K: "Cladribine/ATL Study Group, Japan. Phase II study of cladribine (2-chlorodeoxyadenosine) in relapsed or refractory adult T-cell leukemia-lymphoma"Int J Hematl.. 77. 512-517 (2003)

Tobinai K：“克拉屈滨/ATL 研究小组，日本。克拉屈滨（2-氯脱氧腺苷）治疗复发或难治性成人 T 细胞白血病-淋巴瘤的 II 期研究”Int J Hematl.. 77. 512-517 (2003)

Leukemogenesis of adult T-cell leukemia.

成人 T 细胞白血病的白血病发生。

• 发表时间: 2003
• 期刊: Int J Hematol 78
• 作者: Yasunaga J-I.;Yoshida M.;Takeda S.;Yasunaga J-I.;Satou Y.;Okayama A.;M Yasunaga J-I.;Matsuoka M.;Matsuoka M.;Nishimura M.;Yasunaga J-I.
• 通讯作者: Yasunaga J-I.