Promoter hypermethylation of the bone morphogenetic protein-6 gene in malignant lymphoma.
OBJECTIVE
Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-beta 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.


METHODS
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).


CONCLUSIONS
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.
Daibata
Masanori
M
Department of Hematology, Kochi Medical School, Kochi University, Kochi, Japan. daibatam@kochi-u.ac.jp
Nemoto
Yuiko
Y
Bandobashi
Kentaro
K
Kotani
Norihiro
N
Kuroda
Masayuki
M
Tsuchiya
Mutsumi
M
Okuda
Heiwa
H
Takakuwa
Tetsuya
T
Imai
Shosuke
S
Shuin
Taro
T
Taguchi
Hirokuni
H
D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D008223:Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
C525816:BMP6 protein, human; D014408:Biomarkers, Tumor; D055418:Bone Morphogenetic Protein 6; D019485:Bone Morphogenetic Proteins