Publication:
Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.

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Abstract
BACKGROUND AND OBJECTIVES Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies. DESIGN AND METHODS In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. RESULTS The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). INTERPRETATIONS AND CONCLUSION: The methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome.
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Journal Article;
MeSH Terms
Medical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::CpG Islands
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Nucleotidyltransferases::RNA Nucleotidyltransferases::RNA Helicases::DEAD-box RNA Helicases
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::DNA Methylation
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Epigenesis, Genetic
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Gene Expression Regulation, Neoplastic
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins::Interferons
Medical Subject Headings::Diseases::Hemic and Lymphatic Diseases::Hematologic Diseases::Bone Marrow Diseases::Myeloproliferative Disorders::Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Medical Subject Headings::Check Tags::Male
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Neoplasm Proteins
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Piperazines
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Diagnosis::Prognosis
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Genetic Structures::Genome::Genome Components::Genes::Gene Components::Regulatory Elements, Transcriptional::Promoter Regions, Genetic
Medical Subject Headings::Chemicals and Drugs::Heterocyclic Compounds::Heterocyclic Compounds, 1-Ring::Pyrimidines
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Nucleic Acid Amplification Techniques::Polymerase Chain Reaction::Reverse Transcriptase Polymerase Chain Reaction
Medical Subject Headings::Anatomy::Urogenital System::Genitalia::Genitalia, Male::Testis
Medical Subject Headings::Chemicals and Drugs::Biological Factors::Antigens::Antigens, Neoplasm
DeCS Terms
CIE Terms
Keywords
Cancer testis antigens, Hypomethylation, CML, HAGE, Leucemia mielogenosa crónica BCR-ABL positiva, Regiones promotoras genéticas, Interferones, Pirimidinas, Metilación del ADN
Citation
Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, San Jose-Eneriz E, et al. Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia. Haematologica. 2007 ; 92(2):153-62