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• W2000406589 abstract "In cutaneous T-cell lymphomas (CTCLs) defects in Fas-mediated apoptosis have been suggested to be involved in disease pathogenesis. Decreased or absent Fas expression has been reported in a significant proportion of CTCL patients, but the molecular mechanisms of such impaired Fas expression have hardly been investigated to date. In this issue, Jones et al. show that defective Fas expression is attributable to positional methylation of the Fas gene. In cutaneous T-cell lymphomas (CTCLs) defects in Fas-mediated apoptosis have been suggested to be involved in disease pathogenesis. Decreased or absent Fas expression has been reported in a significant proportion of CTCL patients, but the molecular mechanisms of such impaired Fas expression have hardly been investigated to date. In this issue, Jones et al. show that defective Fas expression is attributable to positional methylation of the Fas gene. Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin’s lymphomas characterized by the clonal proliferation of skin homing T cells. The most common CTCLs are mycosis fungoides (MF) and Sézary syndrome (SzS), an aggressive leukemic variant of MF. The tumor cells in MF and SzS exhibit a T helper type 2 (Th2) cytokine profile that contributes to associated immunosuppression. Biologic response modifiers such as IFN-α, IFN-γ, and IL-12, which stimulate T helper 1 responses, have significant therapeutic effects in SzS. Appropriate Fas-mediated cell death is crucial for T-cell homeostasis. The elimination of activated T cells proceeds via activation-induced cell death (AICD), a process that is dependent on Fas signaling and subsequent apoptosis. In the absence of adequately controlled AICD, T cells are likely to accumulate. In both mice and humans, Fas gene mutations leading to defective Fas signaling result in lymphoproliferative disorders as a consequence of lymphocyte accumulation (Rieux-Laucat et al., 1995Rieux-Laucat F. Le Deist F. Hivroz C. et al.Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.Science. 1995; 268: 1347-1349Crossref PubMed Scopus (1139) Google Scholar). Because in certain types of CTCL (MF, SzS) tumor cells have been demonstrated to be long-lived, activated CD4 + cells, defects in Fas-mediated apoptosis have recently been suggested to play a role in the accumulation of tumor T cells that occurs in each disease. Defective Fas signaling has been implicated in the resistance to apoptosis induced by chemotherapeutic drugs. Furthermore, the lack of functional Fas signaling allows tumor cells to escape immune surveillance, facilitating disease progression. Several mechanisms contributing to Fas signaling defects in cancer have been described, including suppressed Fas expression at mRNA and protein levels (Bullani et al., 2002Bullani R.R. Wehrli P. Viard-Leveugle I. et al.Frequent downregulation of Fas (CD95) expression and function in melanoma.Melanoma Res. 2002; 12: 263-270Crossref PubMed Scopus (61) Google Scholar; Petak et al., 2003Petak I. Danam R.P. Tillman D.M. et al.Hypermethylation of the gene promoter and enhancer region can regulate Fas expression and sensitivity in colon carcinoma.Cell Death Differ. 2003; 10: 211-217Crossref PubMed Scopus (74) Google Scholar). Epigenetic silencing of the Fas gene promoter has been shown to be regulated by Ras (Gazin et al., 2007Gazin C. Wajapeyee N. Gobeil S. et al.An elaborate pathway required for Ras-mediated epigenetic silencing.Nature. 2007; 449: 1073-1077Crossref PubMed Scopus (224) Google Scholar). Furthermore, mutations or deletions in Fas have been found to cause autoimmune lymphoproliferative syndromes in both mice and humans (Rieux-Laucat et al., 1995Rieux-Laucat F. Le Deist F. Hivroz C. et al.Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity.Science. 1995; 268: 1347-1349Crossref PubMed Scopus (1139) Google Scholar). Finally, the Fas signaling pathway can be modulated by intracellular apoptosis inhibitors such as cellular FLICE-like inhibitory protein and Bcl-2 family members. Decreased expression of Fas on peripheral blood CD4+ T lymphocytes in MF and SzS was first reported in 2000 (Dereure et al., 2000Dereure O. Portales P. Clot J. et al.Decreased expression of Fas (APO-1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T-cell lymphomas.Br J Dermatol. 2000; 143: 1205-1210Crossref PubMed Scopus (41) Google Scholar; Zoi-Toli et al., 2000Zoi-Toli O. Vermeer M.H. De Vries E. et al.Expression of Fas and Fas-ligand in primary cutaneous T-cell lymphoma (CTCL): association between lack of Fas expression and aggressive types of CTCL.Br J Dermatol. 2000; 143: 313-319Crossref PubMed Scopus (79) Google Scholar). More recently, we (Contassot et al., 2008Contassot E. Kerl K. Roques S. et al.Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression.Blood. 2008; 111: 4780-4787Crossref PubMed Scopus (59) Google Scholar) and others (Braun et al., 2007Braun F.K. Fecker L.F. Schwarz C. et al.Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells.J Invest Dermatol. 2007; 127: 2425-2437Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar; Wu et al., 2009Wu J. Nihal M. Siddiqui J. et al.Low FAS/CD95 expression by CTCL correlates with reduced sensitivity to apoptosis that can be restored by FAS upregulation.J Invest Dermatol. 2009; 129: 1165-1173Crossref PubMed Scopus (72) Google Scholar) have reported that a decrease, and sometimes a complete loss, of Fas expression is a relatively frequent event in lymphocytes from patients with SzS. In our cohort of 16 SzS patients, 9 were resistant to FasL, which in 4 patients was caused by a loss of Fas expression. In MF, resistance to FasL-induced apoptosis has already been attributed to mutations in the Fas gene (Dereure et al., 2002Dereure O. Levi E. Vonderheid E.C. et al.Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin.J Invest Dermatol. 2002; 118: 949-956Crossref PubMed Scopus (80) Google Scholar; Nagasawa et al., 2004Nagasawa T. Takakuwa T. Takayama H. et al.Fas gene mutations in mycosis fungoides: analysis of laser capture-microdissected specimens from cutaneous lesions.Oncology. 2004; 67: 130-134Crossref PubMed Scopus (19) Google Scholar) and to the expression of a nonfunctional Fas splice variant (van Doorn et al., 2002van Doorn R. Dijkman R. Vermeer M.H. et al.A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma.Cancer Res. 2002; 62: 5389-5392PubMed Google Scholar) (Table 1). Until now, the exact mechanisms leading to the decrease—or loss—of Fas expression on CD4+ tumor cells from SzS patients has not been investigated. In this issue, Jones et al. show that Fas expression at both mRNA and protein levels is decreased on CD4+ cells in a significant proportion (21/47, 45%) of SzS patients as compared with CD4+ cells from healthy donors. Notably, the authors demonstrate that the underexpression of Fas is attributable to positional methylation of the Fas CpG island and not to functional mutations within the transcribed Fas region.Table 1Genetic and epigenetic alterations of Fas in CTCLsCauseDiseaseFrequency (%)ReferencesFAS mutationsMF6/44 patients (14)Dereure et al., 2002Dereure O. Levi E. Vonderheid E.C. et al.Infrequent Fas mutations but no Bax or p53 mutations in early mycosis fungoides: a possible mechanism for the accumulation of malignant T lymphocytes in the skin.J Invest Dermatol. 2002; 118: 949-956Crossref PubMed Scopus (80) Google ScholarMF3/16 patients (18)Nagasawa et al., 2004Nagasawa T. Takakuwa T. Takayama H. et al.Fas gene mutations in mycosis fungoides: analysis of laser capture-microdissected specimens from cutaneous lesions.Oncology. 2004; 67: 130-134Crossref PubMed Scopus (19) Google ScholarNonfunctional splice variantMFCD30-PCLTCL3/7 patients (43)4/8 patients (50)van Doorn et al., 2002van Doorn R. Dijkman R. Vermeer M.H. et al.A novel splice variant of the Fas gene in patients with cutaneous T-cell lymphoma.Cancer Res. 2002; 62: 5389-5392PubMed Google ScholarPromoter hypermethylationSzS21/47 (45)Jones et al., 2010Jones C.L. Wain E.M. Chu C.-C. et al.Downregulation of Fas gene expression in Sézary syndrome is associated with promoter hypermethylation.J Invest Dermatol. 2010; 130: 1116-1125Abstract Full Text Full Text PDF PubMed Scopus (47) Google ScholarMF, mycosis fungoides; PCLTCL, primary cutaneous large T-cell lymphoma; SzS, Sézary syndro Open table in a new tab MF, mycosis fungoides; PCLTCL, primary cutaneous large T-cell lymphoma; SzS, Sézary syndro It is known that cancer cells exhibit aberrant gene expression and, in the past decade, epigenetics research has revealed that, together with histone acetylation, DNA hypermethylation of CpG-rich promoter sequences is associated with the inactivation of several tumor suppressor genes in several types of cancers (Esteller, 2007Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps.Nat Rev Genet. 2007; 8: 286-298Crossref PubMed Scopus (1573) Google Scholar). In the human genome, approximately half of the gene-promoter regions contain CpG-rich regions, the so-called CpG islands (Bird, 1986Bird A.P. CpG-rich islands and the function of DNA methylation.Nature. 1986; 321: 209-213Crossref PubMed Scopus (2899) Google Scholar; Gardiner-Garden and Frommer, 1987Gardiner-Garden M. Frommer M. CpG islands in vertebrate genomes.J Mol Biol. 1987; 196: 261-282Crossref PubMed Scopus (2537) Google Scholar). The majority of the CpG islands are located in the 5 untranslated region and the first exon of genes. Such CpG-rich regions are prone to hypermethylation. DNA methylation consists of the addition of a methyl group to the carbon 5 position of the cytosine ring in the CpG dinucleotide by DNA methyltransferase, resulting in the formation of methylcytosine (Holliday and Grigg, 1993Holliday R. Grigg G.W. DNA methylation and mutation.Mutat Res. 1993; 285: 61-67Crossref PubMed Scopus (247) Google Scholar). Although CpG-island hypermethylation profiles vary with tumor type (Costello et al., 2000Costello J.F. Fruhwald M.C. Smiraglia D.J. et al.Aberrant CpG-island methylation has non-random and tumour-type-specific patterns.Nat Genet. 2000; 24: 132-138Crossref PubMed Scopus (1118) Google Scholar), such epigenetic alterations play important roles in the pathogenesis of cancer. These studies have shown not only that genes involved in the control of cell growth are affected but also that promoter hypermethylation affects apoptosis regulator genes. Analysis of DNA hypermethylation is already used in selected instances as a marker for the diagnosis of cancer and as a surrogate marker for the prediction of responses to chemotherapy. Therapeutic strategies aiming to revert DNA methylation and histone acetylation exist. Histone deacetylase (HDAC) inhibitors reverse some of the aberrant epigenetic alterations associated with cancer, resulting in re-expression of silenced genes involved in growth arrest, terminal differentiation, and/or apoptosis in carcinoma cells. Recently, HDAC inhibitors (vorinostat and romidepsin) have also been evaluated for the treatment of refractory CTCLs. Responses rates ranging from 24 to 34% were reported for all MF disease stages, and similar responses were reported for SzS (Olsen et al., 2007Olsen E.A. Kim Y.H. Kuzel T.M. et al.Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma.J Clin Oncol. 2007; 25: 3109-3115Crossref PubMed Scopus (817) Google Scholar; Piekarz et al., 2009Piekarz R.L. Frye R. Turner M. et al.Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous t-cell lymphoma.J Clin Oncol. 2009; 27: 5410-5417Crossref PubMed Scopus (594) Google Scholar). The observation that CTCLs can respond favorably to HDAC inhibitors strongly supports the idea that epigenetic alterations may play an important role in the pathogenesis of these malignancies (Batty et al., 2009Batty N. Malouf G.G. Issa J.P. Histone deacetylase inhibitors as anti-neoplastic agents.Cancer Lett. 2009; 280: 192-200Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar; Piekarz et al., 2009Piekarz R.L. Frye R. Turner M. et al.Phase II multi-institutional trial of the histone deacetylase inhibitor romidepsin as monotherapy for patients with cutaneous t-cell lymphoma.J Clin Oncol. 2009; 27: 5410-5417Crossref PubMed Scopus (594) Google Scholar). Given the apparent importance of CpG island methylation in the pathogenesis of hematological malignancies, the use of 5-azacitidine and 5-aza-2-deoxycytidine, two hypomethylating agents, has also been considered for hematological malignancies, either alone or in combination with HDAC inhibitors. The two drugs cited above have been shown to have significant activity in patients with high-risk myelodysplastic syndromes (Fenaux et al., 2007Fenaux P. Raza A. Mufti G.J. et al.A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome.Blood. 2007; 109: 4158-4163Crossref PubMed Scopus (99) Google Scholar). Studies have provided evidence for epigenetic instability and promoter methylation in CTCLs, leading to the deregulation of tumor suppressor genes involved in cell cycle control (p15, p16, p73, CHFR), DNA repair (MGMT), and apoptosis signaling (TMS1, p73) (Scarisbrick et al., 2002Scarisbrick J.J. Woolford A.J. Calonje E. et al.Frequent abnormalities of the p15 and p16 genes in mycosis fungoides and Sezary syndrome.J Invest Dermatol. 2002; 118: 493-499Crossref PubMed Scopus (91) Google Scholar). Taken together with the data reported by Jones et al. in this issue, it appears that further investigation of the use of demethylating agents in CTCLs, including SzS, is warranted. Recent studies have shown that restoration of Fas expression on tumor cells can also be achieved either by the in vitro exposure of tumor cells to IFN-α or IFN-γ or by Fas gene transfer (Contassot et al., 2008Contassot E. Kerl K. Roques S. et al.Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression.Blood. 2008; 111: 4780-4787Crossref PubMed Scopus (59) Google Scholar; Wu et al., 2009Wu J. Nihal M. Siddiqui J. et al.Low FAS/CD95 expression by CTCL correlates with reduced sensitivity to apoptosis that can be restored by FAS upregulation.J Invest Dermatol. 2009; 129: 1165-1173Crossref PubMed Scopus (72) Google Scholar). Such approaches could represent a strategy for counteracting apoptosis resistance in SzS; however, the downregulation of Fas expression on SzS CD4+ cells is not the only cause of resistance to FasL-mediated apoptosis in CTCLs. In this context, it has recently been shown that the intracellular apoptosis inhibitor cFLIP is overexpressed in Fas-expressing apoptosis-resistant CD4+ tumor cells in CTCLs, thus providing another molecular mechanism for resistance to death receptor-mediated apoptosis (Braun et al., 2007Braun F.K. Fecker L.F. Schwarz C. et al.Blockade of death receptor-mediated pathways early in the signaling cascade coincides with distinct apoptosis resistance in cutaneous T-cell lymphoma cells.J Invest Dermatol. 2007; 127: 2425-2437Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar; Contassot et al., 2008Contassot E. Kerl K. Roques S. et al.Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression.Blood. 2008; 111: 4780-4787Crossref PubMed Scopus (59) Google Scholar). Furthermore, the observation that certain Bcl-2 family members, such as Mcl-1, are also overexpressed in CTCLs suggests that they may also contribute to the resistance to death receptor-mediated apoptosis (Zhang et al., 2003Zhang C.L. Kamarashev J. Qin J.Z. et al.Expression of apoptosis regulators in cutaneous T-cell lymphoma (CTCL) cells.J Pathol. 2003; 200: 249-254Crossref PubMed Scopus (51) Google Scholar). Thus, in CTCLs, tumor T cells may acquire resistance to Fas-mediated apoptosis via several independent mechanisms. The findings reported by Jones et al. are of importance when considering the optimal therapeutic strategy to initiate in a given patient with CTCL. Because methylation of the Fas promoter is not observed in all patients with SzS, the use of hypomethylating drugs may not be equally effective in restoring sensitivity to Fas-mediated apoptosis in all patients. Thus, not only is the existence of potent hypomethylating agents important, but their use will require a “personalized” medical approach in which these agents are employed in patients having tumors with positional methylation of the Fas CpG island." @default.
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• W2000406589 title "Epigenetic Causes of Apoptosis Resistance in Cutaneous T-Cell Lymphomas" @default.
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