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Bone morphogenetic proteins (BMPs), which belong to the transforming growthfactor-β superfamily, are multifunctional signaling molecules that have becomeof increasing interest in cancer research. Recent observations suggest that alterationsin BMPs and BMP signaling are associated with tumorigenesis and disease progressionin various types of malignancies. This study investigated the methylation statusof the BMP6 gene promoter in various types of plasma cell proliferative disordersby combined bisulfite restriction analysis. While BMP6 methylation was not detectedin any samples from monoclonal gammopathies of undetermined significance, intramedullarymultiple myeloma (MM), plasma cell leukemia or solitary plasmacytoma, both casestudies and cell line studies showed that multiple extramedullary plasmacytoma(MEP) consistently carried a methylated BMP6 promoter. The BMP6 methylation-positiveMEP was an aggressive form of MM with extremely high levels of serum lactate dehydrogenase(LDH). Bisulfite sequencing analysis confirmed intensive methylation at CpG sitesof the BMP6 promoter region. The methylation of BMP6 was correlated with decreasedlevels of mRNA transcripts. Expression of BMP6 was restored by the demethylatingagent 5-aza-2'-deoxycytidine, suggesting that the methylation is associated withtranscriptional silencing. Our study implied that BMP6 promoter methylation isnot a common event in MMs, but occurs in aggressive MEP. These findings warrantfurther investigation to clarify whether BMP6 methylation together with elevatedLDH could be a marker of poor prognosis in MEP patients who should be consideredfor early intensive treatment.

Promoter methylation of the bone morphogenetic protein 6 gene in multiple myeloma