This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roman-Gomez, J. Articles by Torres, A. Search for Related Content PubMed PubMed Citation Articles by Roman-Gomez, J. Articles by Torres, A.

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

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.

This article has been cited by other articles:

				J. Greiner, L. Bullinger, B.-a. Guinn, H. Dohner, and M. Schmitt Leukemia-Associated Antigens Are Critical for the Proliferation of Acute Myeloid Leukemia Cells Clin. Cancer Res., November 15, 2008; 14(22): 7161 - 7166. [Abstract] [Full Text] [PDF]

				M. Perez-Ilzarbe, O. Agbulut, B. Pelacho, C. Ciorba, E. S. Jose-Eneriz, M. Desnos, A. A. Hagege, P. Aranda, E. J. Andreu, P. Menasche, et al. Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium Eur J Heart Fail, November 1, 2008; 10(11): 1065 - 1072. [Abstract] [Full Text] [PDF]

				C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF]