beta2-Microglobulin mutations, HLA class I antigen loss, and tumor progression in melanoma

The Journal of Clinical Investigation
D J HicklinS Ferrone

Abstract

The potential negative impact of HLA class I antigen abnormalities on the outcome of T cell-based immunotherapy of melanoma has prompted us to investigate the mechanisms underlying lack of HLA class I antigen expression by melanoma cell lines Me18105, Me9923, and Me1386. Distinct mutations in the beta2-microglobulin (beta2m) gene were identified in each cell line which result in loss of functional beta2m. In Me18105 cells, an aberrant splicing mechanism caused by an A--> G point mutation in the splice acceptor site of intron 1 of the beta2m gene, deletes 11 bp from the beta2m mRNA creating a shift in the reading frame. In Me9923 cells a 14-bp deletion in exon 2 and in Me1386 cells a CT deletion in exon 1 of the beta2m gene produce a frameshift mutation. The beta2m gene mutations identified in Me18105, Me9923, and Me1386 cells were also detected in the surgically removed melanoma lesions from which the cell lines originated. Transfection of each melanoma cell line with a wild-type beta2m gene restored HLA class I antigen expression and, in Me18105 cells, recognition by Melan-A/MART-1-specific, HLA-A2-restricted cytotoxic T lymphocytes. Interestingly, the beta2m mutation present in Me9923 cells that were derived from a metastatic...Continue Reading

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