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

Abstract

Background and ObjectivesCancer 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 MethodsIn 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. ResultsThe TCC-S cell line showed demethylation of HAGE that was associated with overexpression 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 ConclusionThe 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. (p210), which has abnormal tyrosine-kinase activity that is central to the pathogenesis of the disease.1 Treatment of CML has been notably improved by imatinib mesylate, a potent tyrosinekinase inhibitor that blocks the kinase activity of p210, thus inhibiting proliferation of Ph'-positive progenitors. 2In the past 5 years, the results of imatinib treatment of CML have established this drug as the first-line therapy for CML patients.3 However, both the persistence of molecular disease in most imatinib-treated patients, as well as the observation that discontinuation of the drug usually results in a rapid loss of the response, indicate that it is unlikely that imatinib alone can cure CML. 2,3An alternative attempt to target CML cells is an active, specific immunotherapy (e.g. a vaccine). In fact, because of the unique amino acid sequence of p210 at the fusion point, the protein is a tumor-specific antigen to which an immune response can be induced. In some studies it has been shown that peptides derived from the p210 fusion point (b3a2) can bind to several HLA class I and class II molecules and thus generate peptidespecific dendritic cells (DC) and cytotoxic T lymphocyte (CTL) responses in vitro. 4,5 Preliminary clinical data suggest that the addition of a b3a2-specific vaccine to b3a2-CML patients treated with conventional treatment might favor a furt...

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