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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.

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