Epigenetic dysregulation of secreted Frizzled-related proteins in multiple myeloma.
We analysed the clinical impact of epigenetic dysregulation of the Wnt pathway in malignant plasma cell disorders. In multiple myeloma (MM) cell lines, aberrant promoter hypermethylation of the secreted Frizzled-related protein (SFRP) genes was a common event, and hypermethylation of SFRP1,-2 and -5 was associated with transcriptional silencing. Among 76 primary patient samples, the frequency of aberrant methylation was 35.5% for SFRP1, 52.6% for SFRP2, 1.3% for SFRP4 and 6.9% for SFRP5. Hypermethylation of SFRP1 and -2 genes was detected in monoclonal gammopathy of undetermined significance and all MM stages including plasma cell leukaemia (PCL), while SFRP5 methylation was restricted to advanced MM stages and PCL. Our data indicate that epigenetic silencing of Wnt antagonists is an early event in MM pathogenesis and that SFRP5 hypermethylation may play a role in disease progression.
Jost
E
E
Medizinische Klinik IV, Universitaetsklinikum Aachen, RWTH Aachen, Germany. ejost@ukaachen.de
Gezer
D
D
Wilop
S
S
Suzuki
H
H
Herman
J G
JG
Osieka
R
R
Galm
O
O
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007952:Leukemia, Plasma Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D016019:Survival Analysis; D051153:Wnt Proteins / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; D005136:Eye Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D013447:Sulfites; D051153:Wnt Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C109618:SFRP2 protein, human; C118723:SFRP4 protein, human; C118511:SFRP5 protein, human; C009279:sodium bisulfite