Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells

Abstract

By presenting immunogenic peptides at the cell surface, major histocompatibility complex (MHC) class II molecules play a key role in the control of adaptive immune responses. Whether expressed constitutively or induced by interferon-g, expression of MHC class II molecules is regulated via coactivator class II transactivator (CIITA); moreover, suppression of their expression is one mechanism by which cancer cells escape host immunity. In this study, we surveyed the relationship between the expression of one MHC class II antigen, HLA -DR, and its coactivators in a group of haematopoietic cell lines, and explored the role of the aberrant DNA methylation in silencing HLA-DR expression. Among 26 cell lines studied, HLA-DR expression was lost from eight T-cell and two myeloid leukaemia cell lines, and this loss was closely associated with suppression of CIITA-PIV expression. Notably, nine of the 10 cell lines that lost CIITA-PIV expression showed methylation of the gene's 5 0 CpG island. Thus, DNA methylation is believed to inhibit the expression of MHC class II molecules in haematopoietic tumour cells by silencing its coactivator, CIITA-PIV. Furthermore, methylation of CIITA-PIV was detected in seven of 32 primary acute myeloid leukaemia specimens, indicating that epigenetic alteration is not a cell line-specific phenomenon. Collectively, these data suggest that, by suppressing expression of MHC class II molecules, epigenetic inactivation of CIITA provides a survival advantage to a subset of haematopoietic tumours.

CIITA methylation and decreased levels of HLA-DR in tumour progression

“…From this standpoint, we recommend that the authors will clarify the relation of CIITA methylation status to constitutive expression of HLA-DR in a larger cohort of haematopoietic tumour. On the basis of their finding (Morimoto et al, 2004) and our present finding, in our opinion, methylation status of CIITA could be a therapeutic target combined with interferon-gamma for preventing the progression of haematopoietic tumour and HLA-DR may be superior to CIITA as a marker for progression of haematopoietic tumour.Additionally, tumour HLA-DR might have a function other than the antigen-presenting function. Recently, Altomonte et al (2003) showed a possible involvement of HLA-DR in a signalling pathway linked to cell adhesion in melanoma cells.…”

“…In this regard, elegant work by Morimoto et al (2004) could provide a therapeutic strategy against various malignancies. The authors stated that, by suppressing the expression of MHC class II molecules, epigenetic inactivation of CIITA provided a survival advantage to a subset of haematopoietic tumours (Morimoto et al, 2004); however, they did not investigate the relation between levels of CIITA and HLA-DR and tumour progression.…”

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We read with interest the article of Morimoto et al (2004) that investigated the relation of epigenetic inactivation of CIITA with levels of HLA-DR, one of the MHC class II genes, in haematopoietic tumour cells.Recent DNA microarray studies have showed that decreased levels of MHC class II molecules are associated with high metastatic potential and/or poor prognosis, not only in haematopoietic tumour (Rimsza et al, 2004) but also in several adenocarcinomas (Ramaswamy et al, 2003) and hepatocellular carcinoma (HCC) (Iizuka et al, 2003), suggesting the common role of MHC class II molecules in tumour progression. In this regard, elegant work by Morimoto et al (2004) could provide a therapeutic strategy against various malignancies.

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“…In this regard, elegant work by Morimoto et al (2004) could provide a therapeutic strategy against various malignancies. The authors stated that, by suppressing the expression of MHC class II molecules, epigenetic inactivation of CIITA provided a survival advantage to a subset of haematopoietic tumours (Morimoto et al, 2004); however, they did not investigate the relation between levels of CIITA and HLA-DR and tumour progression.Our recent DNA microarray study showed that decreased levels of HLA-DRA gene were related to recurrence of HCC (Iizuka et al, 2003). We also confirmed that levels of HLA-DR protein by tumour cells were related to recurrence of HCC (unpublished data).…”

“…We read with interest the article of Morimoto et al (2004) that investigated the relation of epigenetic inactivation of CIITA with levels of HLA-DR, one of the MHC class II genes, in haematopoietic tumour cells.…”