A new β<sub>2</sub> microglobulin mutation found in a melanoma tumor cell line

Pérez, Beatriz Ferrán; Benítez, Ricardo; Fernández, María Angustias Parejo; Oliva, Maria R.; Soto, José Luís; Serrano, Salvio; Nevot, Miguel Ángel López; Garrido, Federico

doi:10.1034/j.1399-0039.1999.530607.x

Cited by 48 publications

(41 citation statements)

References 6 publications

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“…We demonstrated that the second ␤ 2 -microglobulin gene is deleted. Comparisons with ␤ 2 -microglobulin mutations in other tumor cell lines suggest a mutation hot spot in exón 1 [22]. Figure 3 summarizes the ␤2-microglobulin mutations already reported.…”

Section: Phenotype Imentioning

confidence: 99%

“…␤ 2 -microglobulin gene alterations are a molecular finding associated with this total loss of HLA phenotype in melanoma [24], colorectal tumors [23], and lymphoma [29]. Certain cell lines are representative of this phenotype; including Daudi lymphoma, FO-1 melanoma, AUMA melanoma, LoVo colon carcinoma, and other tumors [22]. In this context, we have described a new ␤ 2 -microglobulin mutation in a melanoma cell line (GR 34) originated at our laboratory.…”

Section: Phenotype Imentioning

confidence: 99%

“…MHC molecules can be lost at any step required for HLA synthesis, transport, or expression on the cell surface [19,20]. Indeed, there are reports of heavy chain and ␤ 2 -microglobulin gene mutations [21][22][23][24], alterations in regulatory factors induced by cis-trans mechanism [25], alterations in glycosylation and transport [26] and HLA gene deletions associated with loss of heterozygocity (LOH) [27].…”

Section: Altered Mhc Class I Phenotypes In Tumorsmentioning

confidence: 99%

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The HLA crossroad in tumor immunology

Algarra¹,

Cabrera²,

Garrido³

2000

Human Immunology

134

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ABSTRACT:It is generally accepted that human and experimental tumor cells can lose major histocompatibility complex (MHC) class I molecules. These human leukocyte antigen (HLA) losses are detected when the primary tumor breaks the basal membrane, invades the surrounding tissues, and starts to metastasize. These altered HLA class I phenotypes probably constitute the major tumor escape mechanism facing anti-tumor T-cell mediated responses. Thus, it is important to characterize these phenotypes in clinical tumor samples, analyze the mechanism(s) responsible for them, and counsel patients before and during peptide anti-cancer immunotherapy. The present paper summarizes the most relevant altered HLA class I phenotypes found in human tumor samples, indicates their frequency, and outlines the mechanisms implicated. This review also points out that the natural killer (NK) escape mechanism of HLA class I deficient cancer cells is yet to be defined. Knowledge accumulated to date reveals that HLA class I molecules are an important crossroad in tumor immunology. Human Immunology 61, 65-73 (2000).

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Section: Phenotype Imentioning

confidence: 99%

Section: Phenotype Imentioning

confidence: 99%

Section: Altered Mhc Class I Phenotypes In Tumorsmentioning

confidence: 99%

See 1 more Smart Citation

The HLA crossroad in tumor immunology

Algarra¹,

Cabrera²,

Garrido³

2000

Human Immunology

134

View full text Add to dashboard Cite

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“…In fact, other mechanisms (␤2m inactivation, TAP/LMP downregulation, altered DNA-binding factors and oncogene overexpression) are observed more frequently and also contribute to a similar phenotype. [2][3][4][5][6] In particular, alterations caused by those mechanisms involving structural alterations to ␤2m lead to irreversible losses that will not respond to treatment with IFN-␥ or demethylation.…”

Section: Dear Sirmentioning

confidence: 99%

Multiple mechanisms are responsible for the alteration in the expression of HLA class I antigens in melanoma

Ruiz‐Cabello

Traversari

Garrido

2003

Intl Journal of Cancer

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“…However, total loss of h2m expression can only result from two mutational events affecting both alleles. Previous studies suggested that loss of one b2m gene contributes to h2m deficiency (19,20). We therefore asked whether and how abnormalities of chromosome 15, to which the b2m gene maps, contribute to the loss of h2m expression in HLA class I-deficient melanoma cells.…”

mentioning

confidence: 99%

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

Paschen

Arens

Sucker

et al. 2006

Clinical Cancer Research

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Purpose:Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8 + Tcells, is known to be caused by mutations in the h2-microglobulin (b2m) gene. We asked whether abnormalities of chromosome 15, harboring the b2m gene on 15q21, in addition to b2m gene mutations, are causative for the HLA class I^negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the h2m-negative metastatic melanoma tissues of four different patients and analyzed them for b2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the b2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions.Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) b2m gene mutations.Melanoma cells can be effectively eradicated in vivo by the cytotoxic activity of HLA class I-restricted tumor antigenspecific CD8 + T cells as recently shown in clinical trials of adoptive T-cell transfer (1, 2). However, these studies also showed that adoptively transferred T cells infiltrating the metastasis not only act as cytotoxic immune effectors but also as immune editors (3, 4) selecting for tumor cell variants that escape immune surveillance by down-regulation of antigen expression (1). Besides antigen down-regulation, other properties of melanoma cells that interfere with T-cell effector function have been described, such as release of immunosuppressive cytokines (5, 6), release of Fas ligand-bearing microvesicles (7), and alterations in the surface presentation of HLA class I molecules (8-10).HLA class I molecules are heterodimeric noncovalently associated complexes consisting of the constant h2-microglobulin (h2m) light chain and the variable HLA heavy a chain. Irreversible alterations in the HLA class I phenotype of melanoma cells, such as loss of a single HLA allele, an HLA locus, or an HLA haplotype, are generally caused by

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A new β₂ microglobulin mutation found in a melanoma tumor cell line

Cited by 48 publications

References 6 publications

The HLA crossroad in tumor immunology

The HLA crossroad in tumor immunology

Multiple mechanisms are responsible for the alteration in the expression of HLA class I antigens in melanoma

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

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A new β2 microglobulin mutation found in a melanoma tumor cell line

Cited by 48 publications

References 6 publications

The HLA crossroad in tumor immunology

The HLA crossroad in tumor immunology

Multiple mechanisms are responsible for the alteration in the expression of HLA class I antigens in melanoma

The Coincidence of Chromosome 15 Aberrations and β2-Microglobulin Gene Mutations Is Causative for the Total Loss of Human Leukocyte Antigen Class I Expression in Melanoma

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A new β₂ microglobulin mutation found in a melanoma tumor cell line