Analysis of the methylated genes in hematological malignancies

骨形态发生蛋白(BMP)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作用仍不清楚。对淋巴瘤组织中BMP-6基因启动子甲基化进行了研究。我们研究了BMP-6启动子甲基化及其基因在不同组织类型的90例原发淋巴瘤和30株淋巴瘤细胞系中的表达。同时评估了BMP-6启动子高甲基化对临床结果的影响。在淋巴瘤的亚群中，BMP-6在表观遗传学上失活。这种沉默在弥漫性大B细胞淋巴瘤(DLBCL)和Burkitt淋巴瘤(BL)中出现频率较高，并与BMP-6启动子异常甲基化有关。60%(21/35)的DLBCL和100%(7/7)的DLBCL、83%(5/6)的BL和86%(12/14)的BL细胞发生甲基化。相比之下，其他组织学类型的原发淋巴瘤，包括霍奇金淋巴瘤、滤泡性淋巴瘤、套细胞淋巴瘤、不明外周T细胞淋巴瘤和血管免疫母细胞T细胞淋巴瘤，几乎没有检测到甲基化(1/49；2%)。去甲基化试剂5-氮-2‘-脱氧胞苷可恢复BMP-6的表达。BMP-6启动子高甲基化是BMP-6表达缺失的原因。在DLBCL中，BMP-6启动子高甲基化与无瘤生存期(P=0.014)和总生存期(P=0.038)的降低有统计学意义。多变量分析显示甲基化状态是预测无病生存期(P=0.022)和总生存期(P=0)的独立预后因素。046)。侵袭性淋巴瘤中BMP-6启动子高甲基化的频率较高，可能与淋巴瘤的组织学类型有关。BMP-6启动子甲基化可能成为预测DLBCL发病风险的一个新的生物标志物。

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.