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

• Published in: Haematologica (Roma) Vol. 92; no. 2; pp. 153 - 162
• Main Authors: Roman-Gomez, Jose, Jimenez-Velasco, Antonio, Agirre, Xabier, Castillejo, Juan A, Navarro, German, San Jose-Eneriz, Edurne, Garate, Leire, Cordeu, Lucia, Cervantes, Francisco, Prosper, Felipe, Heiniger, Anabel, Torres, Antonio
• Format: Journal Article
• Language: English
• Published: Pavia Haematologica 01-02-2007; Ferrata Storti Foundation
• Subjects: Antigens, Neoplasm - blood; Antineoplastic Agents - pharmacology; Benzamides; Biological and medical sciences; Cell Line, Tumor; CpG Islands; DEAD-box RNA Helicases - genetics; DEAD-box RNA Helicases - physiology; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Imatinib Mesylate; Interferons - therapeutic use; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Piperazines - pharmacology; Prognosis; Promoter Regions, Genetic; Pyrimidines - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Testis - metabolism; Human; Cancer testis antigen; CML; Tumor associated antigen; Hematology; Malignant hemopathy; Gene; HAGE; Chronic myelocytic leukemia; hypomethylation; Epigenetics; Genetics; cancer testis antigens; Methylation
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.10782

From the Hematology Department, Reina Sofia Hospital, Cordoba, Spain (JR-G, JAC, AT); Hematology Department, Carlos Haya Hospital, Malaga, Spain (AJ-V, GN, AH); Hematology Department, Cellular Therapy Area, Clinica Universitaria/School of Medicine, Foundation for Applied Medical Research. University of Navarra, Pamplona, Spain (XA, ESJ-E, LG, LC, FP); Hematology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Spain (FC)
Correspondence: José Roman-Gomez, Hematology Department, Reina Sofia Hospital, Avda. Menendez Pidal s/n. 14004 Cordoba, Spain. E-mail: peperosa{at}teleline.es
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.
Key words: cancer testis antigens, HAGE, hypomethylation, CML.