Frequent expression of HAGE in presentation chronic myeloid leukaemias

Abstract

Cancer testis (CT) antigens provide attractive targets for cancer-specific immunotherapy. Although CT genes are expressed in some normal tissues, such as the testis and in some cases placenta, these immunologically protected sites lack MHC I expression and as such, do not present 'self' antigens to T cells. To date, CT genes have been shown to be expressed in a range of solid tumours, but rarely in haematological malignancies. We have extended previous studies to investigate the expression of a comprehensive range of CT genes (MAGE-A1, -A3, -A6, -A12, BAGE, GAGE, HAGE, LAGE-1, NY-ESO-1 and RAGE) for their expression in a cohort of acute and chronic myeloid leukaemia patient samples. CT expression was not detected in 20 normal bone marrow or peripheral blood stem cell samples. In acute myeloid leukaemia (AML) nine of the 26 (35%) samples analysed expressed one or more of the CT genes with six of the samples (23%) expressing HAGE. In chronic myeloid leukaemia (CML) 24 of 42 (57%) presentation chronic myeloid leukaemia (CML) patient samples expressed one or more CT antigen with 23 expressing HAGE. We have shown that HAGE is frequently expressed in CML, and to a lesser extent in AML patient samples. This is the first demonstration of HAGE gene expression in myeloid leukaemia patients and the frequent expression of HAGE at disease presentation opens up the possibility of early immunotherapeutic treatments.

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

“…HAGE mRNA was previously reported to be expressed in half of 43 CML patients at presentation. 10 However, this study did not verify the methylation status of the HAGE promoter CpG islands. The evidence of HAGE expression, induced by hypomethylation, was provided by the re-expression of HAGE, after treatment with 5-aza-2'-deoxycytidine, in CML cell lines not expressing HAGE.…”

Epigenetics and the plasticity of differentiation in normal and cancer stem cells

“…Different types of cancers, both solid tumors and leukemias, express certain genes that are normally expressed only in germ line cells and are thus called cancer/testis (CT) genes (Adams et al, 2002;Scanlan et al, 2004;Guinn et al, 2005;Simpson et al, 2005). Analysis of global gene expression in different types of human cancers compared to the normal tissue from which the cancers originated, has identified many genes that are overexpressed in the cancers (Okutsu et al, 2002;Ma et al, 2003;Sotiriou et al, 2004;Jarzab et al, 2005;Yu et al, 2005;Lee et al, 2006b).…”

Analogue peptides for the immunotherapy of human acute myeloid leukemia

“…The first group includes cancer-testis antigens (CTAs), so called because of an expression limited to cancer and immunologically protected tissues, such as testis and placenta, which lack MHC class I expression. Examples of these include the Per Arnt Sim Domain containing 1 (PASD1) antigen [10] and the helicase antigen (HAGE) [8]. The second grouping is that of the 'TAA' which, while expressed by tumor cells, are also found in some healthy tissues.…”

“…However, the comparison of a solid tumor and a leukemia/hematological malignancies-only list for ranking antigens would be of interest to the research community [7], allowing reflection on the different weightings of TAAs verus LAAs with a view to their application in clinical trials for solid and liquid tumors, respectively. It appears that many of the antigens expressed with frequencies of note in solid tumors are not expressed frequently in patients with hematological malignancies ( [7,8]), the obvious exception being WT1.…”