Analysis of the methylated genes in hematological malignancies

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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.