Disease relevance of MAGEA3

• These distinctive epigenetic phenotypes of MAGEA1 and MAGEA3 also were observed in pure seminomas and in the seminomatous elements of mixed-type TGCTs [1].
• To shed light on the epigenetic phenotypes among histological subtypes of TGCTs, we investigated the methylation and expression of several cancer testis antigen (CTA) genes (MAGEA1, MAGEA3, and SYCP1) in TGCTs [1].
• The clinical significance of MAGEA3 expression in pancreatic cancer [2].
• Though MAGEA3 expression has been detected in gastrointestinal malignancies, its role in pancreatic ductal adenocarcinoma (PDAC) has not been well established [2].
• Human gene MAGE-3 codes for an antigen recognized on a melanoma by autologous cytolytic T lymphocytes [3].

High impact information on MAGEA3

• Some of them are encoded by genes MAGE-1 and MAGE-3, which are not expressed in normal tissues except in testis [4].
• In a patient vaccinated with a MAGE-3 antigen presented by HLA-A1, we measured the frequencies of anti-vaccine and antitumor T cells in several metastases to evaluate their respective potential contribution to tumor rejection [5].
• These Th1 cells recognized not only peptides, but also DCs loaded with Mage-3 protein, and in case of Mage-3DP4-specific Th1 cells IFN-gamma was released even after direct recognition of viable, Mage-3-expressing HLA-DP4+ melanoma cells [6].
• By stimulating human CD8(+) T lymphocytes with autologous dendritic cells infected with an adenovirus encoding MAGE-3, we obtained a cytotoxic T lymphocyte (CTL) clone that recognized a new MAGE-3 antigenic peptide, AELVHFLLL, which is presented by HLA-B40 [7].
• Since this treatment is known to induce the exchange of the three catalytic subunits of the proteasome to form the immunoproteasome, this result suggested that the processing of this MAGE-3 peptide required the immunoproteasome [7].

Chemical compound and disease context of MAGEA3

• Forty-three germ cell tumors (24 seminomas, six embryonal carcinomas and 13 mixed germ cell tumors), and 10 Leydig cell tumors were selected for study, and standard immunohistochemical techniques were used on formalin-fixed paraffin-embedded tissues using mouse monoclonal antibodies to MAGE-1 (clone M454) and MAGE-3 (clone 57B) antigens [8].
• Finally, 5-aza-2'-deoxycytidine induced a 16-fold increase of MAGE3 expression in Mel 313 melanoma cells expressing constitutively low levels of the antigen, but did not affect that of Mel 275 melanoma cells expressing high baseline levels of MAGE3 [9].
• Furthermore, de novo expression of MAGE3 gene induced by the treatment of Mel 195 melanoma cells with the DNA hypomethylating agent 5-aza-2'-deoxycytidine was associated with a 6%-12% demethylation of selected cytosine-guanine dinucleotides in its promoter [9].
• CONCLUSION: The prognostic value of this method could be improved by combining it with PCR of other melanoma markers (Melan A, Mage 3) or assays of serum markers (S 100 protein or lactate dehydrogenase) [10].
• Furthermore, treatment of melanoma cells expressing the MAGE-3 protein with lactacystin resulted in efficient lysis by MAGE-3271-279-specific CTL [11].

Biological context of MAGEA3

• Analyzing patients with MM (n = 66) for antibody responses against MAGEA3, SSX2, and NY-ESO-1, we found strong antibody responses against CT antigens preferentially in patients who had received allogeneic stem cell transplantation (alloSCT) [12].
• MAGEA3 gene expression was detected by qRT in 25 (44%) patients [2].
• Like MAGE-1, MAGE-3 is composed of three exons and the large open reading frame is entirely located in the third exon [3].
• BACKGROUND & AIMS: The genes MAGE-1 and MAGE-3 both encode melanoma peptide antigens recognized by major histocompatibility complex-restricted cytotoxic T lymphocytes [13].
• Similarly, the CTL lines failed to recognize MAGE-3-negative HLA-A2-positive tumor lines after transfection with the MAGE-3 gene, although they were able to recognize COS-7 cells transfected with MAGE-3 [14].

Anatomical context of MAGEA3

• Gene MAGE-3 is expressed in many tumors of several types, such as melanoma, head and neck squamous cell carcinoma, lung carcinoma and breast carcinoma, but not in normal tissues except for testes [3].
• The cancer germ-line genes MAGE-1, MAGE-3 and PRAME are commonly expressed by human myeloma cells [15].
• We show that malignant plasma cells from the majority of MM patients (n = 21) expressed MAGE-1, MAGE-3 and PRAME [15].
• The significance of MAGE-1 and MAGE-3 proteins in normal spermatogonia and primary spermatocytes will require additional study [8].
• A cytolytic T lymphocyte (CTL)-defined MAGE-3 antigen, corresponding to the MAGE-3 peptide 271-279 associated with the human leukocyte antigen (HLA)-A2 molecule, has been recently identified using T lymphocytes from a normal individual stimulated in vitro with peptide-pulsed autologous antigen-presenting cells [14].

Associations of MAGEA3 with chemical compounds

• Either MAGE-1 or -3 gene expressions were induced in 1 of 3 MAGE-1 negative breast cell lines or 1 of 3 MAGE-3 negative breast cell lines by the treatment with 5-aza-2'-deoxycytidine [16].
• Specifically, the MAGE-3 gene was linked to a leader sequence at its NH2 terminus for secretion and to a cell-binding domain at its COOH terminus for receptor-mediated internalization [17].
• CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies [18].
• Similar stability data were also obtained for MAGE-3, another N-terminal glutamic acid containing CTL peptide in clinical development, leading us to suggest that all N-terminal glutamic acid and probably glutamine-containing CTL peptide epitopes may be stabilized as hydrochloride salts [19].

Physical interactions of MAGEA3

• MAGE peptide binding by HLA-A29 and HLA-B44 was confirmed by photoaffinity labeling with photoreactive MAGE-3 peptide derivatives on C1R.A29 and C1R.B44 cells, respectively [20].
• RESULTS: Using native CLL cells as antigen-presenting cells (APCs), we demonstrate the generation of MDM2-specific T cells in 7/12 CLL patients that recognized specifically the MDM2-derived peptide MDM2(81-88) bound to HLA-A2-dimers while they were inactive against an unrelated MAGE-3 peptide (p = 0.002) [21].

Regulatory relationships of MAGEA3

• All but one of the tumors expressing MAGE-1 also expressed MAGE-3 [22].
• Autologous CD8+ CTL lines generated with cp-DCs produced tumor necrosis factor when stimulated with HLA-A2-binding immunodominant peptides from MelanA/MART1 and MAGE-3 (expressed by MEL-397 cells) but not tyrosinase (absent in MEL-397) [23].
• The CTL responses could thus be induced from unseparated spleen cells in HLA-A2 patients with gastric carcinoma expressing MAGE-3 by stimulating these cells with autologous spleen cells pulsed with HLA-A2-restricted MAGE-3 peptide as antigen-presenting cells and by using keyhole limpet hemocyanin and interleukin-7 for the primary culture [24].
• The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells [18].

Other interactions of MAGEA3

• The antigenic peptide of MZ2-D is a nonapeptide that is encoded by the sequence of MAGE-3 that is homologous to the MAGE-1 sequence coding for the MZ2-E peptide [3].
• Higher homology was found between MAGE-3 and -6 (98% at the nt level) and also between MAGE-4 and -41 (98%) [25].
• Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P-value range: 0.05-0.001) [26].
• In contrast, photoaffinity labeling of HLA-A29 was efficiently inhibited by these as well as by the MAGE-3 and MAGE-6 nonapeptides [20].
• Among 46 primary lung cancers, high expression rates were found for MAGE-3 (41%, 19/46), and SSX-4 (35%, 16/46) [27].

Analytical, diagnostic and therapeutic context of MAGEA3

• Total RNA from paraffin-embedded pancreatic tumors was extracted and assessed for MAGEA3 gene expression by an optimized probe-based quantitative real-time RT-PCR (qRT) assay [2].
• Immunohistochemistry (IHC) was performed and confirmed MAGEA3 protein in PDAC specimens [2].
• MAGE-3 encoded antigens may therefore have a wide applicability for specific immunotherapy of melanoma patients [3].
• MAGE-1 and MAGE-3 represent targets for specific immunotherapy because they encode peptide antigens which are recognised by cytotoxic T lymphocytes (CTL) when presented by HLA class I molecules, and pilot clinical trials with these peptides are currently in progress [28].
• Immunoblotting and immunohistochemical analysis were performed to confirm the expression of MAGE-3 gene product in HCC [29].

References