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Molecular Analysis of the HLA-A2 Antigen Loss by Melanoma Cells SK-MEL-29.1.22 and SK-MEL-29.1.29¹

Department of Microbiology and Immunology, New York Medical College, Valhalla, New York 10595 [Z. W., N. M., S. F.]; III Department of Internal Medicine, Johannes Gutenberg University, 55101 Mainz, Germany [B. S.]; Tumor Immunology Program, German Cancer Research Centre, 69120 Heidelberg, Germany [F. M.]; and Medical Clinic, Hematology-Oncology, Krankenhaus Nordwest, 60488 Frankfurt, Germany [A. K.]

Due to the potential clinical relevance of HLA class I antigen losses in melanoma cells and the scanty information about the molecular mechanisms underlying these defects, we have characterized the cause of the HLA-A2 antigen loss by autologous melanoma cell lines SK-MEL-29.1.22 and SK-MEL-29.1.29. Both cell lines have structural defects of HLA-A2 genes, which cause lack of their transcription. In SK-MEL-29.1.22 cells the 5'-flanking region, exon 1, intron 1, and a region at the 5' end of exon 2 of the HLA-A2 gene are deleted. The breakpoint of the HLA-A2 gene, which is recombined with a DNA fragment of unknown origin, was localized between two GTTCG sequence repeats at position 101 of exon 2. These repeats may provide the sequence basis for misalignment in the process of DNA deletion. In SK-MEL-29.1.29 cells, loss of HLA-A2 antigens, as well as of HLA-B44 and HLA-Cw5 alleles, is caused by the loss of one copy of chromosome 6. Down-regulation of the expressed HLA class I alleles in the two HLA-A2 loss variants and in the parental cells was found to be associated with a low TAP1 expression and a reduced function of peptide transporters. Therefore, multiple defects result in loss or down-regulation of HLA class I alleles in SK-MEL-29.1.22 and SK-MEL-29.1.29 melanoma cells.

¹ Supported by National Cancer Institute (United States Public Health Service, Department of Health and Human Services) Grants CA51814 and CA67108.

² Present Address: The Experimental Medicine Section, Oral Infection and Immunity Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland (Z.W.)

³ To whom requests for reprints should be addressed. Phone: (914) 594-4175; Fax: (914) 594-4176.

Received 11/ 7/97. Accepted 3/17/97.

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