CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia.
B-cell chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of mature neoplastic B cells indicating disruption of apoptosis. Restriction Landmark Genome Scanning was done to identify novel target genes silenced by CpG island methylation in CLL. Secreted frizzled-related protein 4 (SFRP4), a negative regulator of the Wnt signaling pathway, was found to be frequently methylated in CLL samples. Wnt signaling has been shown to control normal apoptotic behavior and is required for normal B-cell development whereas aberrant activation of this pathway has been observed in CLL. We show aberrant DNA methylation and silencing of SFRP4, as well as of additional SFRP family members, in primary CLL samples. Induction of their expression in a dose-dependent manner following treatment with a demethylating agent, 5-aza-2'-deoxycytidine, was shown. Of the five SFRP family members studied in detail, SFRP1 was hypermethylated and down-regulated in all CLL patient samples studied, suggesting that this epigenetic event is a critical step during leukemogenesis. Our results suggest that silencing of SFRPs by CpG island methylation is one possible mechanism contributing to aberrant activation of Wnt signaling pathway in CLL.
Liu
Te-Hui
TH
Department of Molecular Virology, Immunology, and Medical Genetics, Division of Human Cancer Genetics, The Ohio State University, 420 West 12th Avenue, Columbus, OH 43210, USA.
Raval
Aparna
A
Chen
Shih-Shih
SS
Matkovic
Jennifer J
JJ
Byrd
John C
JC
Plass
Christoph
C
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic; D018899:CpG Islands; D019175:DNA Methylation; D000077209:Decitabine; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000503:physiopathology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D001374:Azacitidine; D000077209:Decitabine; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051153:Wnt Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins; C118723:SFRP4 protein, human