Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies in tumor immunology indicate that malignant cells frequently express normal testicular-specific proteins. Because these proteins show restricted normal tissue distribution, they are usually highly immunogenic and may be potential targets for immunotherapy. In the present study, we have used a pair of sequence-specific primers in reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis to demonstrate that the X-linked gene encoding SPAN-Xb is expressed in multiple myeloma and other hematologic malignancies such as chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), and acute myeloid leukemia (AML). RT-PCR analysis demonstrates that SPAN-Xb is a cancer/testis antigen and shows a restricted normal tissue expression. It is not expressed in any normal tissue except testis. SPAN-Xb recombinant protein was produced and used in enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. High-titer immunoglobulin G (IgG) antibodies, of IgG3 or IgG2 subclass, against SPAN-Xb were detectable in the sera of these patients. In contrast, SPAN-Xb mRNA or antibodies could not be detected in any of the healthy donors. There was a good correlation between SPAN-Xb gene expression and B-cell immune responses. These results suggest the in vivo immunogenicity of the SPAN-Xb protein. The presence of high-titer IgG responses suggests that the B-cell responses are likely to have been generated with CD4 T-cell cognitive help. Based on these data, we conclude that SPAN-Xb is a novel member of the family of cancer/testis antigens aberrantly expressed by, and capable of inducing, immune responses in patients with multiple myeloma and other hematologic malignancies.
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PMID:Gene expression and immunologic consequence of SPAN-Xb in myeloma and other hematologic malignancies. 1239 89

Normal testicular-specific proteins are frequently aberrantly expressed by tumor cells. Based on this, we have investigated Semenogelin 1, a major protein of human semen coagulum thought to be highly specific to seminal vesicles, in leukemic cells. Using reverse transcription-polymerase chain reaction, Semenogelin 1 gene was frequently expressed in chronic myeloid leukemia (5 of 8, 62.5%) and chronic lymphocytic leukemia (5 of 12, 41.7%) but rarely in multiple myeloma (2 of 30, 6.7%). The gene was not expressed in bone marrow or peripheral blood from healthy donors. Semenogelin 1 expression is normally confined to the testis, suggesting that it is a novel Cancer-Testis (CT) antigen. Translation of the mRNA to Semenogelin 1 protein was confirmed by Western blot analysis of tumor cell lysates and by immunocytochemistry. The recombinant Semenogelin 1 protein was used with a control Escherichia coli-derived recombinant protein in ELISA and Western blot analysis to show that high titer IgG antibodies against Semenogelin 1 were detected in some patients, suggesting the in vivo immunogenicity of the protein. Immune responses predicted gene expression by the leukemia cells. Semenogelin 1 was also frequently coexpressed with other CT antigens, Sperm protein 17 and SPAN-Xb. These results therefore indicate that Semenogelin 1 is a novel CT antigen capable of inducing B-cell responses in vivo in chronic leukemias.
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PMID:Pattern of gene expression and immune responses to Semenogelin 1 in chronic hematologic malignancies. 1459 13

SPAN-Xb is a novel cancer-testis antigen in multiple myeloma (MM). In this study, we determined the mechanisms regulating SPAN-Xb expression in MM. SPAN-Xb promoter sequence was first cloned into the CAT-reporter vector to determine the role of promoter methylation in the regulation of gene expression. Tumor cells were treated with 5-azacytidine and a panel of cytokines were used to determine their ability to induce SPAN-Xb expression. Bisulfite conversion with sequence analysis was applied to a panel of tumor cells and normal tissues to correlate the CpG dinucleotide hypomethylation and SPAN-Xb expression. We found that SPAN-Xb promoter function could be silenced by methylation. 5-Azacytidine induced promoter hypomethylation and resulted in SPAN-Xb expression, at both the transcript and protein levels. Hypomethylation of the CpG dinucleotides at positions -310, -307, -299 and -221 within the SPAN-Xb promoter strongly predict for SPAN-Xb expression. Both IL-7 and GM-CSF were also able to upregulate the expression of SPAN-Xb in myeloma cells, but only after the promoter sequence has been hypomethylated. Our results provide the first evidence showing the role of promoter methylation in the primary regulation of SPAN-Xb and the ability of IL-7 and GM-CSF to further enhance SPAN-Xb gene and protein expression in myeloma cells.
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PMID:SPAN-Xb expression in myeloma cells is dependent on promoter hypomethylation and can be upregulated pharmacologically. 1618 75

SPAN-Xb is a novel cancer-testis antigen in multiple myeloma. We recently demonstrated that SPAN-Xb expression in myeloma cells is regulated through promoter methylation and could be upregulated by IL-7 and GM-CSF. In this present study, we set out to investigate the mechanism of SPAN-XB expression and the promoter association with the methyl-CpG binding protein (MeCP2). Elucidation of these interactions is likely shed light on potential therapeutic strategies to upregulate antigen levels for SPAN-Xb-based tumor vaccines. Using a panel of truncated promoter constructs, we localize the core sequence of SPAN-XB promoter to the 73 bp at the 3' end of the promoter, a region within the full length promoter that lacks CpG dinucleotides. Reporter gene expression assays showed that the core promoter function is significantly modulated by the adjacent CpG sequences. Chromatin immunoprecipitation assays revealed a specific association of MeCP2 with the promoter, and MeCP2 binding strongly correlated with repression of SPAN-XB gene. Reactivation of the SPAN-XB gene by 5-azacytidine treatment resulted in the loss of MeCP2 from this site. We, therefore, conclude that SPAN-XB core promoter function in myeloma cells is associated with MeCP2 protein binding and regulated by specific CpG dinucleotide sequences.
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PMID:SPAN-XB core promoter sequence is regulated in myeloma cells by specific CpG dinucleotides associated with the MeCP2 protein. 1703 33

The cancer-testis antigen SPAN-XB has been recently identified in multiple myeloma (MM). In the present study, we identified and characterized for the first time a cytotoxic cellular immune response against SPAN-XB in healthy donors and patients with MM. Using two independent computer algorithms, two SPAN-XB-derived peptides (peptides 624 and 626) with predicted binding to HLA-A2 were identified. To further improve the immunogenicity of peptide 626 we designed a heteroclitic peptide (peptide 627) by modifying one amino acid on the HLA binding position 2 of peptide 626. Using an IFN-gamma Elispot assay we could demonstrate the presence and functional activity of CD8 peptide specific T cells with all tested peptides. By analysis of peripheral blood of 13 healthy donors and five patients with MM peptide specific T-cell precursors specifically recognizing at least one of the tested peptides could be detected and expanded in 9 of 13 of tested donors and 3 of 5 tested patients. Importantly, in two donors specific peptides could be generated against the heteroclitic peptide 627 but not against the native peptide 626. We conclude that SPAN-XB-derived peptides can elicit a consistent CD8 T cell response in healthy donors and patients with MM.
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PMID:Cellular immune responses against the cancer-testis antigen SPAN-XB in healthy donors and patients with multiple myeloma. 1839 29