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Promoter Hypermethylation of the Bone Morphogenetic Protein-6 Gene in Malignant Lymphoma

Author's Affiliations: Departments of ¹ Hematology and Respiratory Medicine, ² Molecular Microbiology and Infections, and ³ Urology, Kochi Medical School, Kochi University, Kochi, Japan; and ⁴ Department of Pathology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

Requests for reprints: Masanori Daibata, Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi 783-8505, Japan. Phone: 81-88-880-2345; Fax: 81-88-880-2348; E-mail: daibatam{at}kochi-u.ac.jp.

Purpose: Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-ß 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.

Experimental Design: We investigated BMP-6 promoter methylation and its gene expression in various histologic types of 90 primary lymphomas and 30 lymphoma cell lines. The effect of BMP-6 promoter hypermethylation on clinical outcome was also evaluated.

Results: BMP-6 was epigenetically inactivated in subsets of lymphomas. The silencing occurred with high frequency in diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma in association with aberrant BMP-6 promoter methylation. The methylation was observed in 60% (21 of 35) of DLBCL cases and 100% (7 of 7) of DLBCL cell lines, and in 83% (5 of 6) of Burkitt's lymphoma cases and 86% (12 of 14) of Burkitt's lymphoma cell lines. In contrast, other histologic types of primary lymphomas studied had little or no detectable methylation (1 of 49; 2%). 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).

Conclusion: BMP-6 promoter was hypermethylated more often in aggressive types of lymphomas, and the hypermethylation is likely to be related to the histologic type of lymphomas. BMP-6 promoter methylation may be a potential new biomarker of risk prediction in DLBCL.