Bone morphogenetic proteins (BMPs), which belong to the transforming growth factor-β superfamily, are multifunctional signaling molecules that have become of increasing interest in cancer research. Recent observations suggest that alterations in BMPs and BMP signaling are associated with tumorigenesis and disease progression in various types of malignancies. This study investigated the methylation status of the BMP6 gene promoter in various types of plasma cell proliferative disorders by combined bisulfite restriction analysis. While BMP6 methylation was not detected in any samples from monoclonal gammopathies of undetermined significance, intramedullary multiple myeloma (MM), plasma cell leukemia or solitary plasmacytoma, both case studies and cell line studies showed that multiple extramedullary plasmacytoma (MEP) consistently carried a methylated BMP6 promoter. The BMP6 methylation-positive MEP was an aggressive form of MM with extremely high levels of serum lactate dehydrogenase (LDH). Bisulfite sequencing analysis confirmed intensive methylation at CpG sites of the BMP6 promoter region. The methylation of BMP6 was correlated with decreased levels of mRNA transcripts. Expression of BMP6 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that the methylation is associated with transcriptional silencing. Our study implied that BMP6 promoter methylation is not a common event in MMs, but occurs in aggressive MEP. These findings warrant further investigation to clarify whether BMP6 methylation together with elevated LDH could be a marker of poor prognosis in MEP patients who should be considered for early intensive treatment.

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