The beta2-microglobulin mRNA in human Daudi cells has a mutated initiation codon but is still inducible by interferon.

Rosa, Frédéric; Berissi, Hanna; Weissenbach, Jean; Maroteaux, Luc; Fellous, Marc; Revel, Michel

doi:10.1002/j.1460-2075.1983.tb01412.x

Cited by 116 publications

(76 citation statements)

References 31 publications

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“…The mutation harbored by the cell line 1074MEL (ATG to ATA) is novel, because it is different from two other initiation codon mutations identified in the Burkitt lymphoma cell line Daudi (ATG to ATC) (34) and in the melanoma cell line LB1622-MEL (ATG to AAG) (35). The nonsense mutation identified in the cell line 1174MEL (TCA to TGA), which introduces a premature stop in codon 31 of exon 2 of the ␤ 2 m gene (31 Ser3 Stop ), is identical with the recently described mutation in the melanoma cell line BB74-MEL (35).…”

Section: Discussionmentioning

confidence: 75%

“…It remains to be determined whether ␤ 2 m-transfected 1259MEL cells are sensitive to lysis by autologous, MA-specific CTL. In contrast, the detection of HLA*0201-MART1 [27][28][29][30][31][32][33][34][35] peptide complexes by the ␤ 2 m-transfected HLA-A2 ϩ 1074MEL cells (1074MEL.␤2.7) suggests that 1074MEL cells carry a functional APM capable of generating HLA class I Ag-restricted, MA-derived peptides. Furthermore, this result parallels our previous finding that ␤ 2 m-transduced 1074MEL cells were susceptible to lysis by HLA-A2 Ag-restricted, MA-specific CTL (8).…”

Section: Discussionmentioning

confidence: 99%

“…The monomeric HLA-A*0201-MART1 27-35 -specific scFv 8.3 was isolated from the human synthetic V H ϩ V L scFv library (Griffin.1 library) by panning with HLA-A*0201-MART1 [27][28][29][30][31][32][33][34][35] peptide complexes (M. Campoli, unpublished results). To construct tetrameric scFv 8.3, monomeric scFv 8.3 were engineered with a C-terminal BirA biotinylation tag (scFv 8.3-BirA) and expressed from ampicillin-resistant bacterial colonies, as previously described (24 -26).…”

Section: Hla-a*0201-melanoma Ag (Ma) Recognized By T Cells (Mart)1 27mentioning

confidence: 99%

“…To determine the functionality of APM in melanoma cells analyzed in this study, we assessed HLA-A*0201-MART1 [27][28][29][30][31][32][33][34][35] …”

Section: Hla-a*0201-mart1 27-35 Complex Expression On ␤ 2 M-transfectmentioning

confidence: 99%

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Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Chang

Campoli

Restifo

et al. 2005

The Journal of Immunology

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Scanty information is available about the mechanisms underlying HLA class I Ag abnormalities in malignant cells exposed to strong T cell-mediated selective pressure. In this study, we have characterized the molecular defects underlying HLA class I Ag loss in five melanoma cell lines derived from recurrent metastases following initial clinical responses to T cell-based immunotherapy. Point mutations in the translation initiation codon (ATG→ATA) and in codon 31 (TCA→TGA) of the β2-microglobulin (β2m) gene were identified in the melanoma cell lines 1074MEL and 1174MEL, respectively. A hot-spot CT dinucleotide deletion within codon 13–15 was found in the melanoma cell lines 1106MEL, 1180MEL, and 1259MEL. Reconstitution of β2m expression restored HLA class I Ag expression in the five melanoma cell lines; however, the HLA-A and HLA-B,-C gene products were differentially expressed by 1074MEL, 1106MEL, and 1259MEL cells. In addition, in 1259MEL cells, the Ag-processing machinery components calnexin, calreticulin, and low m.w. polypeptide 10 are down-regulated, and HLA-A2 Ags are selectively lost because of a single cytosine deletion in the HLA-A2 gene exon 4. Our results in conjunction with those in the literature suggest the emergence of a preferential β2m gene mutation in melanoma cells following strong T cell-mediated immune selection. Furthermore, the presence of multiple HLA class I Ag defects within a tumor cell population may reflect the accumulation of multiple escape mechanisms developed by melanoma cells to avoid distinct sequential T cell-mediated selective events.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Hla-a*0201-melanoma Ag (Ma) Recognized By T Cells (Mart)1 27mentioning

confidence: 99%

“…To determine the functionality of APM in melanoma cells analyzed in this study, we assessed HLA-A*0201-MART1 [27][28][29][30][31][32][33][34][35] …”

Section: Hla-a*0201-mart1 27-35 Complex Expression On ␤ 2 M-transfectmentioning

confidence: 99%

See 2 more Smart Citations

Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Chang

Campoli

Restifo

et al. 2005

The Journal of Immunology

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“…Our explanation for this finding could be that heavy chains recognized by HCA2 antibody (mainly of the HLA-A type) might be more stable at the cell surface in the absence of β2-m than the heavy chains recognized by HC10 (mainly of the HLA-B/C types). The underlying mechanism of β2-m weak expression could involve deletion or mutation in the β2-m gene, in analogy with other well studied tumours (Klein et al, 1967;Rosa et al, 1983;D'Urso et al, 1991;Bicknell et al, 1994). Alternatively, it could result from a post-translational mechanism such as sequestering of the β2-m protein by a viral or other protein, in analogy with the mechanism described for cytomegalovirus down-regulation of MHC class I molecules (Chapman and Bjorkman, 1998).…”

Section: Mhc Class I Expression In Osccsmentioning

confidence: 95%

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

et al. 1999

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Cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells use the secretory pathway of perforin/granzymes to kill their target cells. In contrast to NK cells, CTL responses are MHC class I restricted. In this study we analysed the relative activation of CTL and NK cells in relation with MHC class I expression on oral squamous cell carcinomas (OSCCs). MHC class I expression was investigated in 47 OSCCs by immunohistochemistry using HCA2, HC10 and β2-m antibodies. The presence of CTLs, NK cells, and its activation, was investigated in 21 of these OSCCs using respectively, CD8, CD57 and GrB7 antibodies. The Q-Prodit measuring system was used for quantification of cytotoxic cells. All OSCCs showed weak or absent staining of β2-m on the cell surface. The absence of β2-m was significantly associated with absent expression of MHC class I heavy chain as detected by HC10 antibody ( P = 0.004). In tumour infiltrates CTLs always outnumbered NK cells, as reflected by the ratio CD57/CD8 being always inferior to one (mean: 0.19; SD: 0.15). The proportion of activated cytotoxic cells as detected by granzyme B expression was generally low (mean: 8.6%; SD 8.9). A clear correlation between MHC class I expression and the relative proportion of NK cells/CTLs was not found. This study shows that the majority of OSCCs show weak or absent expression of MHC class I molecules on the cell surface, possibly due to alterations in the normal β2-m pathway. The low proportion of granzyme B-positive CTLs/NK cells indicates that the secretory pathway of cytotoxicity is poor in these patients. The lack of correlation between MHC class I expression and CTL/NK cell activation as detected by granzyme B expression suggests that, next to poor antigen presentation, also local factors seem to determine the final outcome of the cytotoxic immune response. © 1999 Cancer Research Campaign

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Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer

et al. 1996

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The escape of tumor cells from immune recognition is a central problem in tumor immunology. Here, we examined the functional role of somatic beta 2-microglobulin (beta2m) gene mutations in human lung and breast cancers. Using single-strand conformational polymorphism (SSCP) analysis and DNA sequencing, we found mutations in the beta2m gene in 2 of 110 tested lung, colon and breast tumors and tumor cell lines. No mutations were identified in 63 breast cancer tumors, in B-lymphoblastoid cell lines or normal tissues from these or other patients. In these cell lines, beta2m protein was undetectable by Western blot analysis and there was no MHC class I on their cell surface even after treatment with interferon-gamma. Transfection of these tumor cell lines with the beta2m gene, but not addition of purified beta2m protein restored MHC expression without addition of exogenous pepticles, indicating that endogenous beta2m expression is necessary for proper intracellular MHC assembly and stabilization by endogeneous pepticles. Mutation in beta2m caused cell line H2009 to be resistant to specific lysis by influenza virus-specific CTL from HLA matched donors, and transfection of the beta2m gene restored this killing. A small cell lung cancer cell line with low class I expression and with a normal beta2m genomic sequence nonetheless also demonstrated increased class I expression after transfection of the beta2m expression vector alone, indicating that the availability of beta2m may be rate limiting for MHC assembly in this line. Our results indicate that somatic mutations or selective loss of expression of the beta2m gene in human lung cancer is rare, but can cause defective MHC class I expression and function allowing these cells to escape recognition by cytotoxic T cells.

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The beta2-microglobulin mRNA in human Daudi cells has a mutated initiation codon but is still inducible by interferon.

Cited by 116 publications

References 31 publications

Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Immune Selection of Hot-Spot β2-Microglobulin Gene Mutations, HLA-A2 Allospecificity Loss, and Antigen-Processing Machinery Component Down-Regulation in Melanoma Cells Derived from Recurrent Metastases following Immunotherapy

Lack of MHC class I surface expression on neoplastic cells and poor activation of the secretory pathway of cytotoxic cells in oral squamous cell carcinomas

Structural and functional analysis of β2 microglobulin abnormalities in human lung and breast cancer

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