Lack of class I HLA expression in neuroblastoma is associated with high N-myc expression and hypomethylation due to loss of the MEMO-1 locus.
Class I HLA expression is low in neuroblastoma tumours and cell lines. We have recently mapped a modifier of methylation for HLA-C (MEMO-1) to chromosomal bands 1p35-36.1, a region deleted in many neuroblastomas. Hypomethylation of HLA-C is strongly correlated with allelic loss of the MEMO-1 locus. Here, we show that loss of MEMO-1 is associated with hypomethylation of both the 5' and 3' regions of class I HLA loci. We next investigated the relationship between methylation and expression of class I HLA in 28 cell lines of neuroectodermal tumours. Cell lines with hypermethylated HLA-C and HLA-A loci have relatively high expression, while most cell lines with hypomethylated loci have no or a reduced expression. It was reported earlier that high expression of c- or N-myc can suppress class I HLA expression. Remarkably, also N-myc amplification in neuroblastomas is associated with allelic loss of 1p35-36. Therefore, we have analysed the relationships between allelic loss of the MEMO-1 locus, class I HLA methylation and expression, and N-myc amplification and expression. This study shows a tight inter-relationship between these phenomena. Our data suggest a model in which hypomethylation of class I HLA due to loss of the MEMO-1 locus and high N-myc expression could collaborate in the down-regulation of class I HLA expression.
Department of Human Genetics, University of Amsterdam, Academic Medical Centre, The Netherlands.
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NC
Cheng
M
M
Beitsma
A
A
Chan
I
I
Op den Camp
A
A
Westerveld
J
J
Pronk
R
R
Versteeg
D002459:Cell Fusion; D002872:Chromosome Deletion; D005805:Genes, MHC Class I; D016259:Genes, myc; D015234:HLA-A Antigens / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D006801:Humans; D008745:Methylation; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured
D015234:HLA-A Antigens; D015236:HLA-C Antigens; D012333:RNA, Messenger