Global Patterns of Methylation in Sézary Syndrome Provide Insight into the Role of Epigenetics in Cutaneous T-Cell Lymphoma
2016; Elsevier BV; Volume: 136; Issue: 9 Linguagem: Inglês
10.1016/j.jid.2016.05.114
ISSN1523-1747
Autores Tópico(s)T-cell and Retrovirus Studies
Resumovan Doorn et al. have defined the DNA methylomes of Sézary cells based on a genome-wide methylation analysis using the Illumina 450K array platform (Illumina, San Diego, CA). Their results show aberrant DNA methylation patterns in CD4-enriched T cells from peripheral blood samples, patterns that are distinct from those of patients with inflammatory erythroderma and from healthy volunteers. Whereas 7.8% of 473,921 5′-cytosine-phosphate-guanine-3′ (CpG) sites were hypomethylated, 3.2% showed marked enrichment and selection for hypermethylated CpG sites within the proximal region of gene promoters, including some genes that have previously been shown to be hypermethylated in cutaneous T-cell lymphomas (CTCLs), using standard bisulfite modification techniques. van Doorn et al. have defined the DNA methylomes of Sézary cells based on a genome-wide methylation analysis using the Illumina 450K array platform (Illumina, San Diego, CA). Their results show aberrant DNA methylation patterns in CD4-enriched T cells from peripheral blood samples, patterns that are distinct from those of patients with inflammatory erythroderma and from healthy volunteers. Whereas 7.8% of 473,921 5′-cytosine-phosphate-guanine-3′ (CpG) sites were hypomethylated, 3.2% showed marked enrichment and selection for hypermethylated CpG sites within the proximal region of gene promoters, including some genes that have previously been shown to be hypermethylated in cutaneous T-cell lymphomas (CTCLs), using standard bisulfite modification techniques. Clinical Implications•Methylation abnormalities will become relevant to future treatment options for SS.•Methylation abnormalities provide insight into the pathogenesis and epigenetic pathways targeted in SS.•They may lead to the discovery of biomarkers in SS. •Methylation abnormalities will become relevant to future treatment options for SS.•Methylation abnormalities provide insight into the pathogenesis and epigenetic pathways targeted in SS.•They may lead to the discovery of biomarkers in SS. The Leiden group (van Doorn et al., 2016van Doorn R. Sliecker R.C. Boonk S.E. Zoutman W.H. Goeman J.J. Bagot M. et al.Epigenomic analysis of Sézary syndrome defines patterns of aberrant DNA methylation and identifies diagnostic markers.J Invest Dermatol. 2016; 136: 1876-1884Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) identified 126 recurrent genes with hypermethylation of CpG-rich promoters as candidates for transcriptional repression and a potential causal role in the pathogenesis of Sézary syndrome (SS). A comparison with The Cancer Genome Atlas network data of solid tumors showed that the prevalence of methylation abnormalities is significantly higher in SS, suggesting that DNA methylation plays a critical role in the pathogenesis of this T-cell malignancy (Weinstein et al., 2013Weinstein J. Collisson E. Mills G. Shaw K. Ozenberger B. Ellrott K et al.The Cancer Genome Atlas Pan-Cancer analysis project.Nat Genet. 2013; 45: 1113-1120Crossref PubMed Scopus (4139) Google Scholar). Hypermethylation of a series of genes appeared to distinguish SS from inflammatory erythrodermas—notably methylation of the CMTM2 gene, which encodes a chemokine-like factor expressed in testis, bone marrow, and peripheral blood cells—was restricted to SS. Tumor biomarkers are overexpressed because of passenger mutations or epigenetic modifications within cancer cells, but there are no currently validated diagnostic or prognostic biomarkers in CTCL. Although CMTM2 might have diagnostic value, loss of expression is always more challenging to define as a tumor biomarker, and a larger series of SS cases with appropriate age-matched controls will need to be studied, because methylation patterns change with age. Nevertheless, this large data set now provides a rich source of material to inform future studies of CTCL, and it complements the recently published data that define the genomic landscape of SS (Choi et al., 2015Choi J. Goh G. Walradt T. Hong B. Bunick C. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar, da Silva Almeida et al., 2015da Silva Almeida A. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C. et al.The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Kiel et al., 2015Kiel M. Sahasrabuddhe A. Rolland D. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar, Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C. Mah A. et al.Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar, Vaqué et al., 2014Vaqué J. Gómez-López G. Monsálvez V. Varela I. Martinez N. Perez C. et al.PLCG1 mutations in cutaneous T-cell lymphomas.Blood. 2014; 123: 2034-2043Crossref PubMed Scopus (159) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K. Shin J. Zhang X. Xi L. et al.Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar, Woollard et al., 2016Woollard W.J. Pullabhatla V. Lorenc A. Patel V.M. Butler R.M. Bayega A. et al.Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome.Blood. 2016; 127: 3387-3397Crossref PubMed Scopus (77) Google Scholar). It is worth reflecting on the possible causative mechanisms and consequences of these methylation abnormalities and the selection pressures for epigenetic abnormalities in SS and other hematologic malignancies compared with solid tumors. Epigenetic abnormalities in cancer have diverse implications, because these DNA and histone modifications are heritable and they not only affect gene transcription but regulate cell differentiation and reprogramming. Furthermore, the underlying mechanisms controlling epigenomic modifications of DNA and histone proteins are now being elucidated (Figure 1). Although global hypomethylation is a consistent feature of cancer and has been shown to contribute to genomic instability, DNA methylation of CpG islands within gene promoters can lead to gene silencing. The methylation of cytosine residues to 5-methycytosine is mediated by DNA methyltransferases (DNMTs), and gain of function mutations of DNMT3A have been identified frequently in hematologic malignancies, including SS (Choi et al., 2015Choi J. Goh G. Walradt T. Hong B. Bunick C. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar, da Silva Almeida et al., 2015da Silva Almeida A. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C. et al.The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K. Shin J. Zhang X. Xi L. et al.Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar, Whittaker et al., 2010Whittaker S. Demierre M. Kim E. Rook A. Lerner A. Duvic M. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar). Cytosine residues account for approximately 1% of the genome, and 60–80% of cytosines are methylated, but this varies according to the type of tissue and stage of cell differentiation. One of the most common mutations in humans involves a C>T transversion, and this mutational signature can be attributable to spontaneous deamination of methylated cytosine residues. Next-generation sequencing studies have already highlighted that C>T mutations are among the most frequent signature detected in SS, and this might reflect spontaneous deamination of methylated cytosines (da Silva Almeida et al., 2015da Silva Almeida A. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C. et al.The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K. Shin J. Zhang X. Xi L. et al.Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar, Whittaker et al., 2010Whittaker S. Demierre M. Kim E. Rook A. Lerner A. Duvic M. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar). Recently, a second type of DNA methylation has been identified involving 5-hydroxymethylation of cytosine. This is mediated by the ten-eleven translocation (TET) family of proteins and affects only 0.03–0.70% of the genome, but, in contrast to 5-methycytosine, is associated with enhanced gene expression (Rasmussen and Helin, 2016Rasmussen K. Helin K. Role of TET enzymes in DNA methylation, development and cancer.Genes Dev. 2016; 30: 733-750Crossref PubMed Scopus (594) Google Scholar). TET loss-of-function mutations are now recognized as one of the most frequent early genetic abnormalities in hematologic malignancies, including T-cell lymphomas and SS (da Silva Almeida et al., 2015da Silva Almeida A. Abate F. Khiabanian H. Martinez-Escala E. Guitart J. Tensen C. et al.The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.Nat Genet. 2015; 47: 1465-1470Crossref PubMed Scopus (272) Google Scholar, Kiel et al., 2015Kiel M. Sahasrabuddhe A. Rolland D. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar, Ungewickell et al., 2015Ungewickell A. Bhaduri A. Rios E. Reuter J. Lee C. Mah A. et al.Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.Nat Genet. 2015; 47: 1056-1060Crossref PubMed Scopus (209) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K. Shin J. Zhang X. Xi L. et al.Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar, Whittaker et al., 2010Whittaker S. Demierre M. Kim E. Rook A. Lerner A. Duvic M. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar). Furthermore, a constellation of mutations in mature T-cell malignancies, including SS, appear to show selection for genes involved in regulating epigenetic modifications, including isocitrate dehydrogenases, which inhibit TET proteins; ARID1A/B, which form part of chromatin modeling complexes; and MLL genes, which mediate histone methyltransferases (Choi et al., 2015Choi J. Goh G. Walradt T. Hong B. Bunick C. Chen K. et al.Genomic landscape of cutaneous T cell lymphoma.Nat Genet. 2015; 47: 1011-1019Crossref PubMed Scopus (287) Google Scholar, Kiel et al., 2015Kiel M. Sahasrabuddhe A. Rolland D. Velusamy T. Chung F. Schaller M. et al.Genomic analyses reveal recurrent mutations in epigenetic modifiers and the JAK-STAT pathway in Sézary syndrome.Nat Commun. 2015; 6: 8470Crossref PubMed Scopus (150) Google Scholar, Wang et al., 2015Wang L. Ni X. Covington K. Shin J. Zhang X. Xi L. et al.Genomic profiling of Sézary syndrome identifies alterations of key T cell signaling and differentiation genes.Nat Genet. 2015; 47: 1426-1434Crossref PubMed Scopus (232) Google Scholar, Whittaker et al., 2010Whittaker S. Demierre M. Kim E. Rook A. Lerner A. Duvic M. et al.Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.J Clin Oncol. 2010; 28: 4485-4491Crossref PubMed Scopus (543) Google Scholar). CTCL was the first malignancy for which histone deacetylase inhibitors were approved, and perhaps these epigenetic abnormalities might explain why histone deacetylase inhibition had clinical benefit (Weinstein et al., 2013Weinstein J. Collisson E. Mills G. Shaw K. Ozenberger B. Ellrott K et al.The Cancer Genome Atlas Pan-Cancer analysis project.Nat Genet. 2013; 45: 1113-1120Crossref PubMed Scopus (4139) Google Scholar). However, the role of inhibitors of DNA methylation, such as azacitidine, has yet to be explored in CTCL and, as van Doorn et al., 2016van Doorn R. Sliecker R.C. Boonk S.E. Zoutman W.H. Goeman J.J. Bagot M. et al.Epigenomic analysis of Sézary syndrome defines patterns of aberrant DNA methylation and identifies diagnostic markers.J Invest Dermatol. 2016; 136: 1876-1884Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar suggest, combined histone deacetylase and DNA methylation inhibitors seems to be an attractive therapeutic option. In fact, phase II trials of this combination are now open for other mature non-Hodgkin's lymphomas (Lue et al., 2015Lue J. Armengaul J. O'Connor O. Epigenetics and lymphoma: can we use epigenetics to prime or reset chemo-resistant lymphoma programs.Curr Oncol Rep. 2015; 17: 40Crossref PubMed Scopus (11) Google Scholar). An intriguing question arising from this study is why T-cell lymphomas—and indeed, other hematologic malignancies—show a selection pressure for specific patterns of epigenetic modification. First, it is important to recognize that epigenetic modulation is responsible for sustaining the adaptive transcriptional memory for both central and tissue resident memory T cells (Dunn et al., 2015Dunn J. McCuaig R. Tu W.J. Hardy K. Rao S. Multilayered epigenetic mechanisms contribute to transcriptional memory in T lymphocytes.BMC Immunol. 2015; 16: 3-11Crossref PubMed Scopus (16) Google Scholar). Specifically, this provides the means for different T-helper subsets to transcribe inducible genes more rapidly (Antigano and Zaph, 2015Antigano F. Zaph C. Regulation of CD4+ T-cell differentiation and inflammation by repressive histone methylation.Immunol Cell Biol. 2015; 93: 245-252Crossref PubMed Scopus (12) Google Scholar). The Leiden team (van Doorn et al., 2016van Doorn R. Sliecker R.C. Boonk S.E. Zoutman W.H. Goeman J.J. Bagot M. et al.Epigenomic analysis of Sézary syndrome defines patterns of aberrant DNA methylation and identifies diagnostic markers.J Invest Dermatol. 2016; 136: 1876-1884Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar) show evidence that the global methylation pattern in most SS cases is similar to that of inducible regulatory T cells and distinct from that of naive T cells. An opportunity for further study would be to compare methylation patterns from a larger cohort of SS patients with those of activated T-helper subsets from age-matched healthy controls. Such data sets are now becoming publically available. This would enable identification of additional tumor-specific epigenetic changes and putative tumor biomarkers and would enhance our understanding of epigenetic influences on the pathogenesis of SS. The author states no conflict of interest. Epigenomic Analysis of Sézary Syndrome Defines Patterns of Aberrant DNA Methylation and Identifies Diagnostic MarkersJournal of Investigative DermatologyVol. 136Issue 9PreviewSézary syndrome (Sz) is a malignancy of skin-homing CD4+ memory T cells that is clinically characterized by erythroderma, lymphadenopathy, and blood involvement. Distinction of Sz from erythroderma secondary to inflammatory skin diseases (erythrodermic inflammatory dermatosis [EID]) is often challenging. Recent studies identified recurrent mutations in epigenetic enzymes involved in DNA modification in Sz. Here we defined the DNA methylomes of purified CD4+ T cells from patients with Sz, EID, and healthy control subjects. Full-Text PDF Open Archive
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