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Analysis of the methylated genes in hematological malignancies

血液系统恶性肿瘤甲基化基因分析

基本信息

批准号：
18591070
负责人：
DAIBATA Masanori
金额：
$ 2.17万
依托单位：
Kochi University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591070/
关键词：
Methylation Hematological malignancy Malignat lymphoma Epstein-Barr virus Oncogene

项目摘要

Bone morphogenetic proteins (BMPs), belonging to the transforming growth factor-β superfamily, are important regulators of cell growth, differentiation, and apoptosis. The biological effects of BMPs on malignant lymphoma, however, remain unknown. Promoter methylation of the BMP-6 gene in lymphomas was investigated. We investigated BMP-6 promoter methylation and its gene expression in various histological types of 90 primary lymphomas and 30 lymphoma cell lines. The impact of BMP-6 promoter hypermethylation on clinical outcome was also evaluated. BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21/35) of DLBCL cases and 100% (7/7) of DLBCL cell lines, and in 83% (5/6) of BL cases and 86% (12/14) of BL cell lines. In contrast, other histological types of primary lymphomas including Hodgkin lymphoma, follicular lymphoma, mantle cell lymphoma, unspecified peripheral T-cell lymphoma, and angioimmunoblastic T-cell lymphoma, studied, had little or no detectable methylation (1/49; 2%). Expression of BMP-6 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that. BMP-6 promoter hypermethylation is responsible for the loss of BMP-6 expression. The presence of BMP-6 promoter hypermethylation in DLBCL statistically correlated with a decrease in disease-free survival (P= 0.014) and overall survival (P= 0.038). Multivariate analysis showed that the methylation profile was an independent prognostic factor in predicting disease-free survival (P= 0.022) and overall survival (P= 0. 046). BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethyaltion is likely to be related to the histological type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.

骨形态发生蛋白（BMPs）属于转化生长因子-β超家族，是细胞生长、分化和凋亡的重要调节因子。然而，BMPs对恶性淋巴瘤的生物学效应仍不清楚。研究了淋巴瘤中BMP-6基因的启动子甲基化。我们研究了90例原发性淋巴瘤和30例淋巴瘤细胞系中BMP-6启动子甲基化及其基因表达。还评估了BMP-6启动子高甲基化对临床结果的影响。BMP-6在淋巴瘤亚群中表观遗传学失活。这种沉默在弥漫性大B细胞淋巴瘤（DLBCL）和伯基特淋巴瘤（BL）中发生的频率很高，与BMP-6启动子异常甲基化有关。DLBCL和DLBCL细胞系的甲基化率分别为60%（21/35）和100%（7/7）; BL和BL细胞系的甲基化率分别为83%（5/6）和86%（12/14）。相比之下，其他组织学类型的原发性淋巴瘤，包括霍奇金淋巴瘤，滤泡性淋巴瘤，套细胞淋巴瘤，未指明的外周T细胞淋巴瘤和血管免疫母细胞性T细胞淋巴瘤，研究，有很少或没有检测到甲基化（1/49; 2%）。去甲基化剂5-氮杂-2 '-脱氧胞苷可恢复BMP-6的表达，提示BMP-6的表达可能与去甲基化剂5-氮杂-2'-脱氧胞苷的作用有关。BMP-6启动子的高甲基化是导致BMP-6表达缺失的原因。在DLBCL中BMP-6启动子高甲基化的存在与无病生存期（P= 0.014）和总生存期（P= 0.038）的降低具有统计学相关性。多因素分析显示，甲基化谱是预测无病生存期（P= 0. 022）和总生存期（P= 0. 005）的独立预后因素。046）。BMP-6基因启动子在侵袭性淋巴瘤中高甲基化程度较高，且与淋巴瘤的组织学类型有关。BMP-6基因启动子甲基化可能成为预测DLBCL风险的一个新的生物标志物。