FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3087288802> ?p ?o ?g. }

• W3087288802 endingPage "11" @default.
• W3087288802 startingPage "1" @default.
• W3087288802 abstract "•DNA and RNA methylation is implicated in normal and aberrant hematopoiesis.•These epigenetic marks are exploited in cancer to evade immune surveillance.•DNA hypomethylating agents can reactivate innate and adaptive immune responses.•Modulating RNA methylation may enhance activation of the immune system.•Novel DNA/RNA methylation therapies may improve outcomes for hematological cancers. Whilst DNA cytosine methylation is the oldest and most well-studied epigenetic modification, basking in its glory days, it may be soon overshadowed by the new kid on the block: RNA adenosine methylation. This juxtaposition is indeed superficial, and a deep exploration toward the fundamental requirements for these essential epigenetic marks provides a clear perspective on their converging and synergistic roles. The recent discovery that both of these modifications are essential for preventing inappropriate activation of the intracellular innate immune responses to endogenous transcripts has provided a lot of interest in targeting them therapeutically as a means to improve cancer immunogenicity. Here we discuss the potential physiological function for DNA and RNA methylation in normal hematopoiesis and how these pervasive epigenetic marks are exploited in cancer, and provide suggestions for future research with a focus on leveraging this knowledge to uncover novel therapeutic targets. Whilst DNA cytosine methylation is the oldest and most well-studied epigenetic modification, basking in its glory days, it may be soon overshadowed by the new kid on the block: RNA adenosine methylation. This juxtaposition is indeed superficial, and a deep exploration toward the fundamental requirements for these essential epigenetic marks provides a clear perspective on their converging and synergistic roles. The recent discovery that both of these modifications are essential for preventing inappropriate activation of the intracellular innate immune responses to endogenous transcripts has provided a lot of interest in targeting them therapeutically as a means to improve cancer immunogenicity. Here we discuss the potential physiological function for DNA and RNA methylation in normal hematopoiesis and how these pervasive epigenetic marks are exploited in cancer, and provide suggestions for future research with a focus on leveraging this knowledge to uncover novel therapeutic targets. Epigenetics represents a level of functional plasticity afforded to the genome at multiple levels. This is no more highly evident than it is in hematopoiesis, where mutations in epigenetic modifiers contribute to aberrant myeloid expansion and resultant leukemia. Mutations in DNA methylation machinery including DNMT3A and TET2 are by far some of the most prevalent in clonal hematopoiesis and acute myeloid leukemia (AML). More recently, RNA-modifying enzymes including METTL3 and FTO have also been implicated in normal and aberrant hematopoiesis. In this review, we provide an overview of DNA and RNA methylation and insights into how these processes shape hematopoiesis, how perturbations lead to oncogenic transformation, and how their regulation of the immune system can be exploited therapeutically. Methylation of the fifth carbon atom of cytosine nucleotides (5-methylcytosine [5mC]) is the most pervasive epigenetic modification and is highly conserved across the animal kingdom [1Zemach A McDaniel IE Silva P Zilberman D Genome-wide evolutionary analysis of eukaryotic DNA methylation.Science. 2010; 328: 916-919Crossref PubMed Scopus (945) Google Scholar,2Feng S Cokus SJ Zhang X et al.Conservation and divergence of methylation patterning in plants and animals.Proc Natl Acad Sci USA. 2010; 107: 8689-8694Crossref PubMed Scopus (699) Google Scholar]. Similar to histone methylation, DNA methylation has three phases: (1) establishment (de novo methylation), (2) maintenance, and (3) demethylation. The first two phases are mediated by three catalytically active DNA methyltransferases (DNMTs); DNMT1, DNMT3A, and DNMT3B. De novo 5mC is mediated by both DNMT3 proteins [3Okano M Bell DW Haber DA Li E DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.Cell. 1999; 99: 247-257Abstract Full Text Full Text PDF PubMed Scopus (3877) Google Scholar], whereas the role of DNMT1 is primarily to maintain the methylome during cell division [4Gruenbaum Y Cedar H Razin A Substrate and sequence specificity of a eukaryotic DNA methylase.Nature. 1982; 295: 620-622Crossref PubMed Scopus (0) Google Scholar]. The final phase, demethylation, occurs via two major pathways that are not necessarily mutually exclusive: passive and active. The prior occurs when DNMT1 is unable to maintain methylation, whether it be by downregulation of DNMT1 or regulated accessibility, resulting in dilution of DNA methylation with subsequent cell divisions. Active demethylation on the other hand, in mammals, principally involves progressive enzymatic conversion of 5mC by the ten-eleven translocation (TET) family of methylcytosine deoxygenases, which culminates in the restoration of unmodified cytosine via base excision repair [5Ito S D'Alessio AC Taranova OV Hong K Sowers LC Zhang Y Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification.Nature. 2010; 466: 1129-1133Crossref PubMed Scopus (1649) Google Scholar, 6Ito S Shen L Dai Q et al.Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine.Science. 2011; 333: 1300-1303Crossref PubMed Scopus (1951) Google Scholar, 7He YF Li BZ Li Z et al.Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA.Science. 2011; 333: 1303-1307Crossref PubMed Scopus (1619) Google Scholar]. It is important to note that the 5mC oxidized derivatives generated by TETs are functional and not just a byproduct of demethylation [8Spruijt CG Gnerlich F Smits AH et al.Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives.Cell. 2013; 152: 1146-1159Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar,9Raiber EA Portella G Martinez Cuesta S et al.5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells.Nat Chem. 2018; 10: 1258-1266Crossref PubMed Scopus (25) Google Scholar]. The notion that DNMTs lay down methyl moieties on DNA and TETs remove them can instead be perceived as a functionally layered regulatory mechanism that enables plasticity and is acutely tuneable depending on epigenomic context and cellular development. Although this dynamic interplay between DNMT and TET activity should indeed be considered collectively when studying perturbations to DNA methylation, this review focuses mainly on DNMT function and how targeting these proteins therapeutically can improve outcomes for patients with myeloid malignancies. Heavily methylated CpG-rich gene promoters are consistently observed to be transcriptionally silenced [10Weber M Hellman I Stadler MB et al.Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.Nat Genet. 2007; 39: 457-466Crossref PubMed Scopus (1478) Google Scholar]. Given that more than two-thirds of mammalian gene promoters contain CpG islands (CGIs), which are all theoretically susceptible to DNA methylation, the repressive potential of DNA methylation is vast. However, most of these promoters are actively transcribed and devoid of DNA methylation [11Bird A Taggart M Frommer M Miller OJ Macleod D A fraction of the mouse genome that is derived from islands of nonmethylated, CpG-rich DNA.Cell. 1985; 40: 91-99Abstract Full Text PDF PubMed Scopus (432) Google Scholar], which is in part regulated by histone modifications at these loci [12Stadler MB Murr R Burger L et al.DNA-binding factors shape the mouse methylome at distal regulatory regions.Nature. 2011; 480: 490-495Crossref PubMed Scopus (788) Google Scholar]. Although the downstream consequence of promoter DNA methylation is transcriptional repression, the story of how this journey unfolds is, still to this day, incomplete. The 5mC mark itself does not inhibit transcription per se; however, it is known to alter the affinity and specificity of epigenetic regulators for DNA sequences that contain this mark [8Spruijt CG Gnerlich F Smits AH et al.Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives.Cell. 2013; 152: 1146-1159Abstract Full Text Full Text PDF PubMed Scopus (627) Google Scholar,13Iurlaro M Ficz G Oxley D et al.A screen for hydroxymethylcytosine and formylcytosine binding proteins suggests functions in transcription and chromatin regulation.Genome Biol. 2013; 14: R119Crossref PubMed Scopus (199) Google Scholar]. The methyl-binding domain (MBD) family of proteins specifically recognizes and binds methylated DNA to recruit histone deacetylase complex (HDAC), which leads to heterochromatin formation [14Nan X Ng HH Johnson CA et al.Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.Nature. 1998; 393: 386-389Crossref PubMed Scopus (2551) Google Scholar,15Ng HH Zhang Y Hendrich B et al.MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex.Nat Genet. 1999; 23: 58-61Crossref PubMed Scopus (717) Google Scholar]. Methylated gene promoters silenced in this manner are relatively resistant to reactivation and serve as a more secure or locked transcriptional repression state [16Bird A DNA methylation patterns and epigenetic memory.Genes Dev. 2002; 16: 6-21Crossref PubMed Scopus (4751) Google Scholar]. This is dissimilar to the other well-characterized transcriptional repressive marks, such as H3K27me3, which is mediated by polycomb repressive complex 2 (PRC2). Genes silenced by PRC2 are perceived to be more plastic in nature, allowing rapid transition to an active state with a permissive signal [17Voigt P Tee WW Reinberg D A double take on bivalent promoters.Genes Dev. 2013; 27: 1318-1338Crossref PubMed Scopus (432) Google Scholar]. It should be noted that DNA methylation evicts both PRC1 and PRC2 complexes from CGIs. The DNA recruiting factors for each of these complexes (KDM2B for PCR1.1 and PHF1 for PRC2) have been reported to have reduced affinity for methylated DNA, which provides a potential explanation of how DNA methylation evicts them from GGI promoters [18Farcas AM Blackledge NP Sudbery I et al.KDM2B links the polycomb repressive complex 1 (PRC1) to recognition of CpG islands.Elife. 2012; 1: e00205Crossref PubMed Scopus (245) Google Scholar,19Li H Liefke R Jiang J et al.Polycomb-like proteins link the PRC2 complex to CpG islands.Nature. 2017; 549: 287-291Crossref PubMed Scopus (81) Google Scholar]. This phenomenon was originally perceived to be somewhat paradoxical, but when one considers that these two mechanisms of transcriptional repression are simply functionally layered regulatory mechanisms, whereby one is plastic and amenable to change (PRC activity) whilst the other is rigid and more resistant to change (DNA methylation), then this paradox is resolved. The more rigid repressed state formed by DNA methylation and subsequent heterochromatin formation is resistant to perturbations and can only be influenced by privileged pioneering transcription factors, which preferentially bind to methylated DNA [20Hu S Wan J Su Y et al.DNA methylation presents distinct binding sites for human transcription factors.Elife. 2013; 2: e00726Crossref PubMed Scopus (186) Google Scholar, 21Liu Y Olanrewaju YO Zheng Y et al.Structural basis for Klf4 recognition of methylated DNA.Nucleic Acids Res. 2014; 42: 4859-4867Crossref PubMed Scopus (55) Google Scholar, 22Yin Y Morgunova E Jolma A et al.Impact of cytosine methylation on DNA binding specificities of human transcription factors.Science. 2017; 356: eaaj2239Crossref PubMed Scopus (275) Google Scholar]. These pioneering transcription factors, such as the pluripotency factors KLF4 and OCT4, enable lineage-defining transcriptional expression patterns during differentiation [22Yin Y Morgunova E Jolma A et al.Impact of cytosine methylation on DNA binding specificities of human transcription factors.Science. 2017; 356: eaaj2239Crossref PubMed Scopus (275) Google Scholar]. DNMT1 and DNMT3B knockout mice die in utero, and DNMT3A knockout mice die postnatally from failure to thrive, highlighting the importance of DNA methylation in development [3Okano M Bell DW Haber DA Li E DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.Cell. 1999; 99: 247-257Abstract Full Text Full Text PDF PubMed Scopus (3877) Google Scholar,23Li E Bestor TH Jaenisch R Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Cell. 1992; 69: 915-926Abstract Full Text PDF PubMed Scopus (2990) Google Scholar]. If DNA methylation is so pervasive and vital for our survival, why is it then that metazoans can develop without it, such as the model experimental organisms Drosophila melanogaster and Caenorhabditis elegans [1Zemach A McDaniel IE Silva P Zilberman D Genome-wide evolutionary analysis of eukaryotic DNA methylation.Science. 2010; 328: 916-919Crossref PubMed Scopus (945) Google Scholar]? It could be argued that more complex metazoans could only evolve intricate tissue-specific networks, which require tightly regulated transcriptional programs, through rigid epigenetic platforms (mediated by DNA methylation) followed by permissive plasticity (site-specific demethylation by privileged transcription factors) to allow tissue specification and differentiation. Indeed, these processes occur in organisms devoid of DNA methylation, but there are perhaps three defining traits of higher metazoans that may define its necessity: the development of (1) complex cognitive function, (2) an expanded repetitive genome populated by endogenous retroviral elements (ERVs), and (3) a highly coordinated intra- and intercellular innate and adaptive immune system. Manifestations of defects in these processes (impaired brain and blood development and reactivated ERVs) are observed in DNMT-deficient mice, providing feasibility to this idea [3Okano M Bell DW Haber DA Li E DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.Cell. 1999; 99: 247-257Abstract Full Text Full Text PDF PubMed Scopus (3877) Google Scholar,23Li E Bestor TH Jaenisch R Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Cell. 1992; 69: 915-926Abstract Full Text PDF PubMed Scopus (2990) Google Scholar]. Furthermore, germline mutant variants of all three DNMTs are associated with neurological and intellectual impairments, and DNMT3B germline variants are associated with immunodeficiency [24Hansen RS Wijmenga C Luo P et al.The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome.Proc Natl Acad Sci USA. 1999; 96: 14412-14417Crossref PubMed Scopus (547) Google Scholar, 25Winkelmann J Lin L Schormair B et al.Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy.Hum Mol Genet. 2012; 21: 2205-2210Crossref PubMed Scopus (149) Google Scholar, 26Tatton-Brown K Seal S Ruark E et al.Mutations in the DNAmethyltransferase gene DNMT3A cause an overgrowth syndrome with intellectual disability.Nat Genet. 2014; 46: 385-388Crossref PubMed Scopus (0) Google Scholar, 27Baets J Duan X Wu Y et al.Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.Brain. 2015; 138: 845-861Crossref PubMed Scopus (0) Google Scholar]. Immune cells constitute one our most complex and diverse cellular systems and have played a significant role in shaping our evolutionary path [28Barreiro LB Quintana-Murci L From evolutionary genetics to human immunology: how selection shapes host defence genes.Nat Rev Genet. 2010; 11: 17-30Crossref PubMed Scopus (297) Google Scholar]. The broad functional diversity of the plethora of cell types that constitute our immune system is highly dependent on various epigenetic mechanisms that regulate and modulate gene expression. These mechanisms are particularly relevant when one considers the notion that all immune cells can be produced by a single hematopoietic stem cell (HSC) in a constitutive manner despite sharing the same genomic content. If we were to imagine this hierarchical differentiation process in the context of Waddington's epigenetic landscape, we then could envisage the multipotent HSC residing at the top of the hill and mature unipotent differentiated immune cells at the bottom, each are formed by taking alternate paths. The forks forged in this path are akin to a cell fate decision in the differentiation process that is ultimately dictated by epigenetic forces. In this metaphorical context, we would propose that DNA methylation forms the peaks enclosing these paths and that the paths (troughs) themselves are formed by active demethylation. In essence, DNA methylation forms the constraints for cellular identity that control the appropriate expression of lineage-defining markers and transcription factors. This is almost universally the case for well-defined cell type-specific factors, such as CD4, CD8, T-bet, and RORgt for T cells, KLF1 for erythrocytes, and PAX5 (enhancer, but not promoter) and CD19 for B cells, just to name a few [29Walter K Bonifer C Tagoh H Stem cell-specific epigenetic priming and B cell-specific transcriptional activation at the mouse Cd19 locus.Blood. 2008; 112: 1673-1682Crossref PubMed Scopus (47) Google Scholar, 30Decker T Pasca di Magliani M McManus S et al.Stepwise activation of enhancer and promoter regions of the B cell commitment gene Pax5 in early lymphopoiesis.Immunity. 2009; 30: 508-520Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 31Ichiyama K Chen T Wang X et al.The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells.Immunity. 2015; 42: 613-626Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 32Sellars M Huh JR Day K et al.Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages.Nat Immunol. 2015; 16: 746-754Crossref PubMed Scopus (50) Google Scholar, 33Li Y Liu D Li Z et al.Role of tissue-specific promoter DNA methylation in regulating the human EKLF gene.Blood Cells Mol Dis. 2018; 71: 16-22Crossref PubMed Scopus (1) Google Scholar]. Active demethylation of the promoters of these lineage-defining factors is observed during their respective lineage commitment, whilst other lineage-defining factors remain silenced by DNA methylation, again reinforcing this notion of DNA methylation controlling cellular identity. Given the importance of our complex and adaptable immune system in our evolutionary path, it is reasonable to suggest that this co-adaptation of DNA methylation has provided a crucial nidus for the development of ever increasingly complex organisms. However, as with many evolutionary co-adapted mechanisms, they come with fitness trade-offs. Pervasive promoter hypermethylation and global hypomethylation constitute a near-universal hallmark of cancer [34Roman-Gomez J Jimenez-Velasco A Agirre X et al.Promoter hypermethylation and global hypomethylation are independent epigenetic events in lymphoid leukemogenesis with opposing effects on clinical outcome.Leukemia. 2006; 20: 1445-1448Crossref PubMed Scopus (0) Google Scholar,35Berman BP Weisenberger DJ Aman JF et al.Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains.Nat Genet. 2011; 44: 40-46Crossref PubMed Scopus (390) Google Scholar]. Whether this observation is causative or the consequence of oncogenesis is still not clear, although some lines of evidence favour the prior. DNMT3A is the most frequently mutated gene in clonal hematopoiesis and is one of the most mutated genes in myeloid malignancies [36Jaiswal S Fontanillas P Flannick J et al.Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med. 2014; 371: 2488-2498Crossref PubMed Scopus (1500) Google Scholar, 37Genovese G Kähler AK Handsaker RE et al.Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.N Engl J Med. 2014; 371: 2477-2487Crossref PubMed Scopus (1229) Google Scholar, 38Papaemmanuil E Gerstung M Bullinger L et al.Genomic classification and prognosis in acute myeloid leukemia.N Engl J Med. 2016; 374: 2209-2221Crossref PubMed Scopus (1200) Google Scholar]. In fact, half of the top six mutated genes in AML are involved in DNA methylation, suggesting that aberrant regulation of this epigenetic mark is important for oncogenic transformation. Indeed, loss of DNMT3A in HSCs leads to seemingly unrestricted self-renewal capacity accompanied by focal hypermethylation and global hypomethylation [39Challen GA Sun D Jeong M et al.Dnmt3a is essential for hematopoietic stem cell differentiation.Nat Genet. 2011; 44: 23-31Crossref PubMed Scopus (612) Google Scholar]. Although this points toward aberrant DNMT activity as the primary culprit of DNA methylation signatures of cancer, promoter hypermethylation and global hypomethylation are frequently observed in the absence of mutations in DNA methylation machinery [40Hinoue T Weisenberger DJ Lange CPE et al.Genome-scale analysis of aberrant DNA methylation in colorectal cancer.Genome Res. 2012; 22: 271-282Crossref PubMed Scopus (429) Google Scholar]. Regardless of the mechanism, these characteristics of myeloid malignancies provided the rationale for the implementation of hypomethylating agents (HMAs), azacitidine and decitabine, in the clinical setting. The purported HMAs along with HDAC inhibitors were the first epigenetic therapies to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer. HMAs are chemical analogues of cytosine, which were originally developed as cytotoxic agents [41Von Hoff DD Slavik M Muggia FM 5-Azacytidine: a new anticancer drug with effectiveness in acute myelogenous leukemia.Ann Intern Med. 1976; 85: 237-245Crossref PubMed Google Scholar]. However, it was quickly established that when incorporated into DNA, they function as an inhibitor of all three DNMTs [42Taylor SM Jones PA Mechanism of action of eukaryotic DNA methyltransferase: use of 5-azacytosine-containing DNA.J Mol Biol. 1982; 162: 679-692Crossref PubMed Scopus (0) Google Scholar,43Oka M Meacham AM Hamazaki T Rodić N Chang LJ Terada N De novo DNA methyltransferases Dnmt3a and Dnmt3b primarily mediate the cytotoxic effect of 5-aza-2′-deoxycytidine.Oncogene. 2005; 24: 3091-3099Crossref PubMed Scopus (0) Google Scholar]. Azacitidine covalently traps DNMTs on DNA, resulting in genomewide DNA hypomethylation through passive dilution of methylated cytosine over multiple generations of cell division [44Palii SS Van Emburgh BO Sankpal UT Brown KD Robertson KD DNA methylation inhibitor 5-aza-2′-deoxycytidine induces reversible genome-wide DNA damage that is distinctly influenced by DNA methyltransferases 1 and 3B.Mol Cell Biol. 2008; 28: 752-771Crossref PubMed Scopus (237) Google Scholar]. It has been widely assumed that the efficacy of azacitidine is driven primarily by its activity as a DNA hypomethylating agent. However, there are potentially four primary mechanisms of action by HMAs that may explain its therapeutic efficacy, but whether all four contribute to the process and if so to what degree remains unknown. The first is cytotoxicity caused by genomic instability and DNA damage as a result of DNMTs being covalently trapped on DNA (Figure 1). Two other possibilities involving DNA hypomethylation include the reactivation of tumor suppressor genes (TSGs) and endogenous retroviruses (ERVs). Finally, it should be noted that azacitidine, a ribonucleoside, is actually more efficiently incorporated into RNA rather than DNA and has been reported to disrupt various aspects of RNA biology including RNA stability, polysome integrity, and RNA methylation [45Aimiuwu J Wang H Chen P et al.RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia.Blood. 2012; 119: 5229-5238Crossref PubMed Scopus (79) Google Scholar]. Whilst cytotoxicity irrefutably mediates a large proportion of the efficacy of HMAs, as cell death can be observed before any changes in DNA methylation [46Juttermann R Li E Jaenisch R Toxicity of 5-aza-2′-deoxycytidine to mammalian cells is mediated primarily by covalent trapping of DNA methyltransferase rather than DNA demethylation.Proc Natl Acad Sci USA. 1994; 91: 11797-11801Crossref PubMed Scopus (0) Google Scholar], the remainder of this review focuses on the potential feasibility of specifically targeting hypomethylation therapeutically. The profound cytotoxic effects of HMAs have made it difficult to dissect the contribution of hypomethylation to their efficacy. A novel nonnucleoside inhibitor of DNMTs was developed, that began to shed light on the matter. RG108 was reported to induce demethylation levels similar to those of azacitidine and robust reactivation of TSG suppressed by DNA methylation, which resulted in cell cycle arrest and apoptosis in multiple solid tumor cell lines [47Schirrmacher E Beck C Brueckner B et al.Synthesis and in vitro evaluation of biotinylated RG108: a high affinity compound for studying binding interactions with human DNA methyltransferases.Bioconjug Chem. 2006; 17: 261-266Crossref PubMed Scopus (0) Google Scholar, 48Graça I Sousa EJ Baptista T et al.Anti-tumoral effect of the non-nucleoside DNMT inhibitor RG108 in human prostate cancer cells.Curr Pharm Des. 2014; 20: 1803-1811Crossref PubMed Scopus (0) Google Scholar, 49Yang L Hou J Cui XH Suo LN Lv Y-W RG108 induces the apoptosis of endometrial cancer Ishikawa cell lines by inhibiting the expression of DNMT3B and demethylation of HMLH1.Eur Rev Med Pharmacol Sci. 2017; 21: 5056-5064PubMed Google Scholar]. However, the magnitude of responses to RG108 is highly variable and modest at best. Nonetheless, this compound, for the first time, illustrated the potential utility of catalytically targeting DNMTs as a therapeutic avenue for cancer without the undesirable byproducts such as DNA damage induced by first-generation HMAs. This discovery paved the way for the development of an improved iteration of nonnucleoside catalytic DNMT inhibitor with superior pharmacokinetics and on-target action, and robust anticancer activity in vitro and in vivo [50Pappalardi MB Cockerill M Handler JL et al.Abstract 2994: discovery of selective, noncovalent small molecule inhibitors of DNMT1 as an alternative to traditional DNA hypomethylating agents.Cancer Rese. 2018; 78 (2994–2994)Google Scholar], which will no doubt provide enormous potential in this therapeutic space. This is particularly exciting given that HMA-induced hypomethylation was recently discovered to reactivate ERVs [51Roulois D Loo Yau H Singhania R et al.DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts.Cell. 2015; 162: 961-973Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar,52Chiappinelli KB Strissel PL Desrichard A et al.Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses.Cell. 2015; 162: 974-986Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar], which are normally suppressed by DNA methylation in most somatic cells [53Rowe HM Friedli M Offner S et al.De novo DNA methylation of endogenous retroviruses is shaped by KRAB-ZFPs/KAP1 and ESET.Development. 2013; 140: 519-529Crossref PubMed Scopus (85) Google Scholar]. Activation of ERVs provides two potentially synergistic modes of anticancer activity. First, is an intracellular innate immune response triggered by the accumulation of dsRNA formed by ERVs following their reactivation [51Roulois D Loo Yau H Singhania R et al.DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts.Cell. 2015; 162: 961-973Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar,52Chiappinelli KB Strissel PL Desrichard A et al.Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses.Cell. 2015; 162: 974-986Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar]. This phenomenon is classically referred to as viral mimicry as it induces a state that phenocopies exogenous virus infection, leading to upregulation of type I and III interferons, other cytokines, and major histocompatibility complex (MHC) class I (Figure 1). Collectively, this cell intrinsic response could potentially synergize with the second anticancer mode of ERV reactivation: extracellular immune surveillance. In addition to the cell intrinsic innate immune response elicited by ERVs, they themselves can produce neoantigens that are efficiently displayed on MHC class I that induce T-cell immunoreactivity [52Chiappinelli KB Strissel PL Desrichard A et al.Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses.Cell. 2015; 162: 974-986Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar,54Smith CC Beckermann KE Bortone DS et al.Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma.J Clin Invest. 2018; 128: 4804-4820Crossref PubMed Scopus (45) Google Scholar]. Although, the seminal discovery of ERV reactivation following exposure to azacitidine provides compelling evidence for both cell intrinsic and extrinsic anticancer effects of this phenomenon, whether this contributes significantly to therapeutic responses in patients is as of yet unknown. To this end, recent studies have found that r" @default.
• W3087288802 created "2020-09-25" @default.
• W3087288802 creator A5005083565 @default.
• W3087288802 creator A5028182005 @default.
• W3087288802 creator A5058771300 @default.
• W3087288802 date "2020-10-01" @default.
• W3087288802 modified "2023-10-16" @default.
• W3087288802 title "The old and the new: DNA and RNA methylation in normal and malignant hematopoiesis" @default.
• W3087288802 cites W1504663603 @default.
• W3087288802 cites W1517594014 @default.
• W3087288802 cites W1607145333 @default.
• W3087288802 cites W1637312052 @default.
• W3087288802 cites W1784857457 @default.
• W3087288802 cites W1905278501 @default.
• W3087288802 cites W1941339056 @default.
• W3087288802 cites W1953890763 @default.
• W3087288802 cites W1967841068 @default.
• W3087288802 cites W1968913698 @default.
• W3087288802 cites W1977123213 @default.
• W3087288802 cites W1978013460 @default.
• W3087288802 cites W1981463058 @default.
• W3087288802 cites W1982393817 @default.
• W3087288802 cites W1984562049 @default.
• W3087288802 cites W1997453048 @default.
• W3087288802 cites W2002458471 @default.
• W3087288802 cites W2007429249 @default.
• W3087288802 cites W2009995861 @default.
• W3087288802 cites W2011400542 @default.
• W3087288802 cites W2014263454 @default.
• W3087288802 cites W2016135634 @default.
• W3087288802 cites W2022140142 @default.
• W3087288802 cites W2022770379 @default.
• W3087288802 cites W2024088186 @default.
• W3087288802 cites W2024848067 @default.
• W3087288802 cites W2025021474 @default.
• W3087288802 cites W2032822109 @default.
• W3087288802 cites W2033408643 @default.
• W3087288802 cites W2037316977 @default.
• W3087288802 cites W2038449573 @default.
• W3087288802 cites W2039053594 @default.
• W3087288802 cites W2040151622 @default.
• W3087288802 cites W2040393829 @default.
• W3087288802 cites W2041191257 @default.
• W3087288802 cites W2043267753 @default.
• W3087288802 cites W2046241907 @default.
• W3087288802 cites W2060446375 @default.
• W3087288802 cites W2063607020 @default.
• W3087288802 cites W2067911388 @default.
• W3087288802 cites W2071930821 @default.
• W3087288802 cites W2085106808 @default.
• W3087288802 cites W2088817968 @default.
• W3087288802 cites W2091235283 @default.
• W3087288802 cites W2094218245 @default.
• W3087288802 cites W2121417064 @default.
• W3087288802 cites W2126816979 @default.
• W3087288802 cites W2127455821 @default.
• W3087288802 cites W2128059998 @default.
• W3087288802 cites W2132762486 @default.
• W3087288802 cites W2134349183 @default.
• W3087288802 cites W2149206894 @default.
• W3087288802 cites W2149858388 @default.
• W3087288802 cites W2149858761 @default.
• W3087288802 cites W2155212164 @default.
• W3087288802 cites W2156891661 @default.
• W3087288802 cites W2157458089 @default.
• W3087288802 cites W2161770318 @default.
• W3087288802 cites W2162942177 @default.
• W3087288802 cites W2165547003 @default.
• W3087288802 cites W2269054226 @default.
• W3087288802 cites W2419140434 @default.
• W3087288802 cites W2563912688 @default.
• W3087288802 cites W2610903912 @default.
• W3087288802 cites W2739087647 @default.
• W3087288802 cites W2743522323 @default.
• W3087288802 cites W2751668414 @default.
• W3087288802 cites W2752092162 @default.
• W3087288802 cites W2754499625 @default.
• W3087288802 cites W2769630486 @default.
• W3087288802 cites W2772792536 @default.
• W3087288802 cites W2776540408 @default.
• W3087288802 cites W2781532633 @default.
• W3087288802 cites W2790270496 @default.
• W3087288802 cites W2883478231 @default.
• W3087288802 cites W2884688483 @default.
• W3087288802 cites W2888593931 @default.
• W3087288802 cites W2895991294 @default.
• W3087288802 cites W2911349862 @default.
• W3087288802 cites W2912048746 @default.
• W3087288802 cites W2921763102 @default.
• W3087288802 cites W2936790196 @default.
• W3087288802 cites W2942816224 @default.
• W3087288802 cites W2967414383 @default.
• W3087288802 cites W2972397772 @default.
• W3087288802 cites W2972933339 @default.
• W3087288802 cites W2981736386 @default.
• W3087288802 cites W2985896683 @default.
• W3087288802 cites W2999012956 @default.
• W3087288802 cites W3003715948 @default.

• next