title: Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n. 14004 Cordoba, Spain. peperosa@teleline.es
authors.forename: Jose
authors.initials: J
authors.lastname: Roman-Gomez
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimenez-Velasco
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Juan A
authors.initials: JA
authors.lastname: Castillejo
authors.forename: German
authors.initials: G
authors.lastname: Navarro
authors.forename: Edurne
authors.initials: E
authors.lastname: San Jose-Eneriz
authors.forename: Leire
authors.initials: L
authors.lastname: Garate
authors.forename: Lucia
authors.initials: L
authors.lastname: Cordeu
authors.forename: Francisco
authors.initials: F
authors.lastname: Cervantes
authors.forename: Felipe
authors.initials: F
authors.lastname: Prosper
authors.forename: Anabel
authors.initials: A
authors.lastname: Heiniger
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
mesh_terms: D000951:Antigens, Neoplasm / Q000097:blood*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D018899:CpG Islands; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000502:physiology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D007372:Interferons / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics* / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013737:Testis / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D007372:Interferons; C412324:DDX43 protein, human; D053487:DEAD-box RNA Helicases