title: Promoter methylation of the bone morphogenetic protein 6 gene in multiple             myeloma.
abstract: 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.
authors.affiliation: Department of Microbiology and Infection, Kochi Medical School,                     Kochi University, Kochi, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Hashida
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Nemoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Imajoh
authors.forename: Masanao
authors.initials: M
authors.lastname: Murakami
authors.forename: Ayuko
authors.initials: A
authors.lastname: Taniguchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Komatsu
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Daibata
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007952:Leukemia, Plasma Cell / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics*; D010265:Paraproteinemias / Q000235:genetics; D010954:Plasmacytoma / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: C525816:BMP6 protein, human; D055418:Bone Morphogenetic Protein 6; D012333:RNA, Messenger