title: Loss of expression of ZAC/PLAGL1 in diffuse large B-cell lymphoma is independent of promoter hypermethylation.
abstract: ZAC/PLAGL1 is a ubiquitously expressed, imprinted tumor suppressor gene located on 6q24, a chromosomal region that is frequently deleted in diffuse large B-cell lymphoma (DLBCL). Like p53, ZAC regulates cell cycle arrest and apoptosis concomitantly, and loss of expression is implicated in tumorigenesis in a variety of different cancers. In most tissues, ZAC transcription is monoallelic and driven by the paternal allele of promoter P1, which lies within a differentially methylated CpG island (DMR). In human blood cells, ZAC transcription is driven by promoter P2, which lies within an unmethylated CpG island and produces biallelic transcripts. Previous reports of epigenetic changes of ZAC in tumors have focused on P1, showing frequent loss of expression caused by paternal allele hypermethylation or loss of heterozygosity (LOH). As ZAC expression in normal B lymphocytes is derived from P2, in DLBCL we analyzed both promoters for gene expression, LOH and abnormal methylation. Loss of P2 transcription was observed in 8 of 11 lymphomas (73%), even though the P2 CpG island remained unmethylated. Three lymphomas showed evidence of LOH (23%), and abnormal methylation of the P1 DMR was observed in an additional four (31%), despite minimal P1 activity in normal B lymphocytes. These data indicate that downregulation of ZAC occurs in DLBCL, as in other cancers. However, unlike P1, transcriptional repression of P2 is not caused by hypermethylation of its associated CpG island in tumors. The mechanistic relationship between altered ZAC expression and epigenetic changes at its promoters thus appears more complex than previously supposed.
authors.affiliation: Section of Genetics, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK. e.m.a.valleley@leeds.ac.uk
authors.forename: Elizabeth M A
authors.initials: EM
authors.lastname: Valleley
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Cordery
authors.forename: Ian M
authors.initials: IM
authors.lastname: Carr
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: MacLennan
authors.forename: David T
authors.initials: DT
authors.lastname: Bonthron
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D018895:Microsatellite Repeats; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C106464:PLAGL1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins