DNA Alkylating Agents Alleviate Silencing of Class II Transactivator Gene Expression in L1210 Lymphoma Cells

Murphy, Shawn P.; Holtz, Renae; Lewandowski, Nicole; Tomasi, Thomas B.; Fuji, Hiroshi

doi:10.4049/jimmunol.169.6.3085

Cited by 27 publications

(20 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DNA methylation is known to be involved in the regulation of CIITA and MHC gene expression in several tumour cell types, including trophoblast-derived cells, a subset of lymphoma cells, and squamous cell carcinoma (Morris et al, 2000;Nie et al, 2001;Murphy et al, 2002;Moreau et al, 2003). Our results suggest that DNA methylation of CIITA-PIV is also a major cause of HLA-DR suppression in haematopoietic tumour cells, especially those derived from T-cells and myeloid cells.…”

Section: Discussionmentioning

confidence: 59%

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

et al. 2004

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 59%

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

et al. 2004

View full text Add to dashboard Cite

show abstract

“…Moreover, the inability to induce MHCII expression in response to IFN-+ is often associated with tumor cells of non-hematopoietic origin [58,[95][96][97][98][99][100]. There is growing evidence that this inability to express MHCII results from epigenetic silencing of the MHC2TA gene [95][96][97][98][99][100][101][102]. The regulatory regions of the MHC2TA gene have been found to be hypermethylated at CpG dinucleotides in MHCII -T cell leukemias, B cell lymphomas and various tumor cells that are unable to express MHCII upon exposure to IFN-+ , including teratocarcinoma, choriocarcinoma, neuroblastoma, erythroleukemia and small cell lung cancer [95,97,[100][101][102].…”

Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

“…There is growing evidence that this inability to express MHCII results from epigenetic silencing of the MHC2TA gene [95][96][97][98][99][100][101][102]. The regulatory regions of the MHC2TA gene have been found to be hypermethylated at CpG dinucleotides in MHCII -T cell leukemias, B cell lymphomas and various tumor cells that are unable to express MHCII upon exposure to IFN-+ , including teratocarcinoma, choriocarcinoma, neuroblastoma, erythroleukemia and small cell lung cancer [95,97,[100][101][102]. Histone deacetylation rather than DNA hypermethylation has been implicated in silencing of MHC2TA expression in several squamous cell carcinoma cell lines [103].…”

Section: Ciita Silencing In Tumor Cellsmentioning

confidence: 99%

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

et al. 2004

View full text Add to dashboard Cite

The class II transactivator (CIITA) has been referred to as the "master control factor" for the expression of MHC class II (MHCII) genes. As our knowledge on the specificity and function of CIITA grows, it is becoming increasingly evident that this sobriquet is entirely justified. First, despite extensive investigations, the major target genes of CIITA remain those implicated in the presentation of antigenic peptides by MHCII molecules. Although other putative target genes have been reported, the contribution of CIITA to their expression remains indirect, controversial or comparatively minor relative to its decisive role as a regulator of MHCII and related genes. Second, the most important parameter dictating MHCII expression is by far the expression pattern of the gene encoding CIITA (MHC2TA). The vast majority of signals that activate or repress MHCII expression under physiological and pathological situations converge on one or more of the three alternative promoters that drive transcription of the MHC2TA gene. In short, with respect to its specificity and its exquisitely controlled pattern of expression, CIITA is by a long stretch the single most important transcription factor for the regulation of genes required for MHCII-restricted antigen-presentation.

show abstract

“…[1][2][3][4][5][6][7][8][9][10][11] For example, in mouse lymphoma cells, DNA-alkylating agents alleviate silencing of class II transactivator gene. 12 Another possible mechanism could be the upregulation and/or neoexpression of costimulatory molecules or cytokines by tumor cells. For example, Mokyr and co-workers 13,14 showed that in the MOPC-315 mouse plasmacytoma, melphalan, mitomycin, and g-irradiation enhanced CD80, INF-b, and TNF-a expression.…”

Section: Introductionmentioning

confidence: 99%

Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells

2004

View full text Add to dashboard Cite

Chemotherapeutic drugs kill cancer cells mainly by direct cytotoxicity, but they might also induce a stronger host immune response by causing the tumor to produce costimulatory cell surface molecules like CD80. We previously reported that in myeloid leukemic cells, c-irradiation induced CD80 expression. In this study, we show that cytosine arabinoside (Ara-C), even at low doses, induced CD80 expression in vitro in mouse DA1-3b leukemic cells, by a mechanism that involved reactive oxygen species. In vivo experiments in the mouse DA1-3b/C3H whole-animal acute myeloid leukemia (AML) model showed that injection of Ara-C induced expression of CD80 and CD86, and decreased expression of B7-H1, indicating that chemotherapy can modify costimulatory molecule expression in vivo, in a way not necessarily observed in vitro. Mouse leukemic cells exposed in vivo to Ara-C were more susceptible to specific cytotoxic lymphocyte (CTL)-mediated killing. Ara-C also induced CD80 or CD86 expression in 14 of 21 primary cultured human AML samples. In humans being treated for AML, induction chemotherapy increased CD86 expression in the leukemic cells. These findings indicate possible synergistic strategies between CTL-based immunotherapy and chemotherapy for treatment. They also suggest an additional mechanism by which chemotherapy can eradicate AML blasts.

show abstract

DNA Alkylating Agents Alleviate Silencing of Class II Transactivator Gene Expression in L1210 Lymphoma Cells

Cited by 27 publications

References 64 publications

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

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

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

Cytosine arabinoside induces costimulatory molecule expression in acute myeloid leukemia cells

Contact Info

Product

Resources

About