Epigenetics: A primer for clinicians

Hotchkiss, 1948, The quantitative separation of purines, pyrimidines, and nucleosides by paper chromatography, J Biol Chem, 175, 315, 10.1016/S0021-9258(18)57261-6 Sober, 1970 Hall, 1972 Gruenbaum, 1981, Methylation of CpG sequences in eukaryotic DNA, FEBS Lett, 124, 67, 10.1016/0014-5793(81)80055-5 Wen, 2014, Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain, Genome Biol, 15, R49, 10.1186/gb-2014-15-3-r49 Ehrlich, 1982, Amount and distribution of 5-methylcytosine in human DNA from different types of tissues of cells, Nucleic Acids Res, 10, 2709, 10.1093/nar/10.8.2709 Lister, 2009, Finding the fifth base: genome-wide sequencing of cytosine methylation, Genome Res, 19, 959, 10.1101/gr.083451.108 Bestor, 1983, Two DNA methyltransferases from murine erythroleukemia cells: purification, sequence specificity, and mode of interaction with DNA, Proc Natl Acad Sci U S A, 80, 5559, 10.1073/pnas.80.18.5559 Hermann, 2004, The Dnmt1 DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites, J Biol Chem, 279, 48350, 10.1074/jbc.M403427200 Vilkaitis, 2005, Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase, J Biol Chem, 280, 64, 10.1074/jbc.M411126200 Okano, 1998, Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases, Nat Genet, 19, 219, 10.1038/890 Stein, 1982, Clonal inheritance of the pattern of DNA methylation in mouse cells, Proc Natl Acad Sci U S A, 79, 61, 10.1073/pnas.79.1.61 Gowher, 2001, Enzymatic properties of recombinant Dnmt3a DNA methyltransferase from mouse: the enzyme modifies DNA in a non-processive manner and also methylates non-CpG [correction of non-CpA] sites, J Mol Biol, 309, 1201, 10.1006/jmbi.2001.4710 Yokochi, 2002, Preferential methylation of unmethylated DNA by mammalian de novo DNA methyltransferase Dnmt3a, J Biol Chem, 277, 11735, 10.1074/jbc.M106590200 Fatemi, 2002, Dnmt3a and Dnmt1 functionally cooperate during de novo methylation of DNA, Eur J Biochem, 269, 4981, 10.1046/j.1432-1033.2002.03198.x Lin, 2002, Murine de novo methyltransferase Dnmt3a demonstrates strand asymmetry and site preference in the methylation of DNA in vitro, Mol Cell Biol, 22, 704, 10.1128/MCB.22.3.704-723.2002 Howell, 2001, Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene, Cell, 104, 829, 10.1016/S0092-8674(01)00280-X Bourc'his, 2001, Dnmt3L and the establishment of maternal genomic imprints, Science, 294, 2536, 10.1126/science.1065848 Hata, 2002, Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice, Development, 129, 1983, 10.1242/dev.129.8.1983 Saitou, 2012, Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells, Development, 139, 15, 10.1242/dev.050849 Okano, 1999, DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development, Cell, 99, 247, 10.1016/S0092-8674(00)81656-6 Oka, 2006, CpG sites preferentially methylated by Dnmt3a in vivo, J Biol Chem, 281, 9901, 10.1074/jbc.M511100200 Hattori, 2004, Preference of DNA methyltransferases for CpG islands in mouse embryonic stem cells, Genome Res, 14, 1733, 10.1101/gr.2431504 Kriaucionis, 2009, The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain, Science, 324, 929, 10.1126/science.1169786 Tahiliani, 2009, Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1, Science, 324, 930, 10.1126/science.1170116 Lian, 2012, Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma, Cell, 150, 1135, 10.1016/j.cell.2012.07.033 Ito, 2010, Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification, Nature, 466, 1129, 10.1038/nature09303 Xu, 2011, Genome-wide regulation of 5hmC, 5mC, and gene expression by Tet1 hydroxylase in mouse embryonic stem cells, Mol Cell, 42, 451, 10.1016/j.molcel.2011.04.005 Bannister, 2011, Regulation of chromatin by histone modifications, Cell Res, 21, 381, 10.1038/cr.2011.22 Zhou, 2011, Charting histone modifications and the functional organization of mammalian genomes, Nat Rev Genet, 12, 7, 10.1038/nrg2905 Jaenisch, 2003, Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals, Nat Genet, 33, 245, 10.1038/ng1089 Goldberg, 2007, Epigenetics: a landscape takes shape, Cell, 128, 635, 10.1016/j.cell.2007.02.006 Waddington, 2012, The epigenotype. 1942, Int J Epidemiol, 41, 10, 10.1093/ije/dyr184 Garcia-Bellido A. Genetic control of wing disc development in Drosophila. Ciba Found Symp 1975;0(29):161–82. Russo, 1996 Bird, 2007, Perceptions of epigenetics, Nature, 447, 396, 10.1038/nature05913 Turner, 2007, Defining an epigenetic code, Nat Cell Biol, 9, 2, 10.1038/ncb0107-2 Compere, 1981, DNA methylation controls the inducibility of the mouse metallothionein-I gene lymphoid cells, Cell, 25, 233, 10.1016/0092-8674(81)90248-8 Lee, 2013, X-inactivation, imprinting, and long noncoding RNAs in health and disease, Cell, 152, 1308, 10.1016/j.cell.2013.02.016 Bird, 1995, Gene number, noise reduction and biological complexity, Trends Genet, 11, 94, 10.1016/S0168-9525(00)89009-5 Harbers, 1981, DNA methylation and gene expression: endogenous retroviral genome becomes infectious after molecular cloning, Proc Natl Acad Sci U S A, 78, 7609, 10.1073/pnas.78.12.7609 Widschwendter, 2004, DNA hypomethylation and ovarian cancer biology, Cancer Res, 64, 4472, 10.1158/0008-5472.CAN-04-0238 Robertson, 2005, DNA methylation and human disease, Nat Rev Genet, 6, 597, 10.1038/nrg1655 Yoder, 1997, Cytosine methylation and the ecology of intragenomic parasites, Trends Genet, 13, 335, 10.1016/S0168-9525(97)01181-5 Muntean, 2012, The pathogenesis of mixed-lineage leukemia, Annu Rev Pathol, 7, 283, 10.1146/annurev-pathol-011811-132434 Herman, 2003, Gene silencing in cancer in association with promoter hypermethylation, N Engl J Med, 349, 2042, 10.1056/NEJMra023075 Ramsahoye, 2000, Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a, Proc Natl Acad Sci U S A, 97, 5237, 10.1073/pnas.97.10.5237 Lister, 2009, Human DNA methylomes at base resolution show widespread epigenomic differences, Nature, 462, 315, 10.1038/nature08514 Ichiyanagi, 2013, Accumulation and loss of asymmetric non-CpG methylation during male germ-cell development, Nucleic Acids Res, 41, 738, 10.1093/nar/gks1117 Smith, 2013, DNA methylation: roles in mammalian development, Nat Rev Genet, 14, 204, 10.1038/nrg3354 Shen, 1994, The rate of hydrolytic deamination of 5-methylcytosine in double-stranded DNA, Nucleic Acids Res, 22, 972, 10.1093/nar/22.6.972 Cooper, 1988, The CpG dinucleotide and human genetic disease, Hum Genet, 78, 151, 10.1007/BF00278187 Sommer, 1992, Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene, FASEB J, 6, 2767, 10.1096/fasebj.6.10.1634040 Rideout, 1990, 5-Methylcytosine as an endogenous mutagen in the human LDL receptor and p53 genes, Science, 249, 1288, 10.1126/science.1697983 Saxonov, 2006, A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters, Proc Natl Acad Sci U S A, 103, 1412, 10.1073/pnas.0510310103 Branciamore, 2010, CpG island clusters and pro-epigenetic selection for CpGs in protein-coding exons of HOX and other transcription factors, Proc Natl Acad Sci U S A, 107, 15485, 10.1073/pnas.1010506107 Li, 1992, Targeted mutation of the DNA methyltransferase gene results in embryonic lethality, Cell, 69, 915, 10.1016/0092-8674(92)90611-F Lei, 1996, De novo DNA cytosine methyltransferase activities in mouse embryonic stem cells, Development, 122, 3195, 10.1242/dev.122.10.3195 Lyko, 1999, Mammalian (cytosine-5) methyltransferases cause genomic DNA methylation and lethality in Drosophila, Nat Genet, 23, 363, 10.1038/15551 Robertson, 2002, DNA methylation and chromatin — unraveling the tangled web, Oncogene, 21, 5361, 10.1038/sj.onc.1205609 Jones, 2009, Rethinking how DNA methylation patterns are maintained, Nat Rev Genet, 10, 805, 10.1038/nrg2651 Penn, 1972, The presence of 5-hydroxymethylcytosine in animal deoxyribonucleic acid, Biochem J, 126, 781, 10.1042/bj1260781 Globisch, 2010, Tissue distribution of 5-hydroxymethylcytosine and search for active demethylation intermediates, PLoS One, 5, 10.1371/journal.pone.0015367 Munzel, 2011, 5-Hydroxymethylcytosine, the sixth base of the genome, Angew Chem Int Ed Engl, 50, 6460, 10.1002/anie.201101547 Bolton, 2009, Superior sulcus tumors with vertebral body involvement: a multimodality approach, J Thorac Cardiovasc Surg, 137, 1379, 10.1016/j.jtcvs.2009.01.015 Tan, 2012, Tet family proteins and 5-hydroxymethylcytosine in development and disease, Development, 139, 1895, 10.1242/dev.070771 Lopez, 2012, Differential effect of three base modifications on DNA thermostability revealed by high resolution melting, Anal Chem, 84, 7336, 10.1021/ac301459x Mendonca, 2014, Hydroxymethylation of DNA influences nucleosomal conformation and stability in vitro, Biochim Biophys Acta, 1839, 1323, 10.1016/j.bbagrm.2014.09.014 Madzo, 2014, Hydroxymethylation at gene regulatory regions directs stem/early progenitor cell commitment during erythropoiesis, Cell Rep, 6, 231, 10.1016/j.celrep.2013.11.044 Rampal, 2014, DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia, Cell Rep, 9, 1841, 10.1016/j.celrep.2014.11.004 Moen, 2015, New themes in the biological functions of 5-methylcytosine and 5-hydroxymethylcytosine, Immunol Rev, 263, 36, 10.1111/imr.12242 Huang, 2010, The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing, PLoS One, 5, 10.1371/journal.pone.0008888 Nestor, 2010, Enzymatic approaches and bisulfite sequencing cannot distinguish between 5-methylcytosine and 5-hydroxymethylcytosine in DNA, Biotechniques, 48, 317, 10.2144/000113403 Wanunu, 2011, Discrimination of methylcytosine from hydroxymethylcytosine in DNA molecules, J Am Chem Soc, 133, 486, 10.1021/ja107836t Luger, 1997, Crystal structure of the nucleosome core particle at 2.8A resolution, Nature, 389, 251, 10.1038/38444 Turner, 2005, Reading signals on the nucleosome with a new nomenclature for modified histones, Nat Struct Mol Biol, 12, 110, 10.1038/nsmb0205-110 Musselman, 2012, Perceiving the epigenetic landscape through histone readers, Nat Struct Mol Biol, 19, 1218, 10.1038/nsmb.2436 Tarakhovsky, 2010, Tools and landscapes of epigenetics, Nat Immunol, 11, 565, 10.1038/ni0710-565 Ruthenburg, 2007, Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark, Mol Cell, 25, 15, 10.1016/j.molcel.2006.12.014 Strahl, 2000, The language of covalent histone modifications, Nature, 403, 41, 10.1038/47412 Iwasaki W, Miya Y, Horikoshi N, Osakabe A, Taguchi H, Tachiwana H, et al. Contribution of histone N-terminal tails to the structure and stability of nucleosomes. FEBS Open Bio 2013;3(0):363–9. Marx, 2006, Molecular biology. Protein tail modification opens way for gene activity, Science, 311, 757, 10.1126/science.311.5762.757a Shogren-Knaak, 2006, Histone H4-K16 acetylation controls chromatin structure and protein interactions, Science, 311, 844, 10.1126/science.1124000 Dhall, 2014, Sumoylated human histone H4 prevents chromatin compaction by inhibiting long-range internucleosomal interactions, J Biol Chem, 289, 33827, 10.1074/jbc.M114.591644 Cedar, 2009, Linking DNA methylation and histone modification: patterns and paradigms, Nat Rev Genet, 10, 295, 10.1038/nrg2540 Feng, 2001, The MeCP1 complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes, Genes Dev, 15, 827 Li, 2002, Chromatin modification and epigenetic reprogramming in mammalian development, Nat Rev Genet, 3, 662, 10.1038/nrg887 Glozak, 2007, Histone deacetylases and cancer, Oncogene, 26, 5420, 10.1038/sj.onc.1210610 Haberland, 2009, The many roles of histone deacetylases in development and physiology: implications for disease and therapy, Nat Rev Genet, 10, 32, 10.1038/nrg2485 Holson, 2011, Chemoproteomics quantifies complexity, Nat Biotechnol, 29, 235, 10.1038/nbt.1804 Bantscheff, 2011, Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes, Nat Biotechnol, 29, 255, 10.1038/nbt.1759 Dekker, 2009, Histone acetyl transferases as emerging drug targets, Drug Discov Today, 14, 942, 10.1016/j.drudis.2009.06.008 Manzo, 2009, Histone acetyltransferase inhibitors and preclinical studies, Expert Opin Ther Pat, 19, 761, 10.1517/13543770902895727 Copeland, 2009, Protein methyltransferases as a target class for drug discovery, Nat Rev Drug Discov, 8, 724, 10.1038/nrd2974 Yang, 2013, Protein arginine methyltransferases and cancer, Nat Rev Cancer, 13, 37, 10.1038/nrc3409 Kubicek, 2007, Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase, Mol Cell, 25, 473, 10.1016/j.molcel.2007.01.017 Chang, 2010, Adding a lysine mimic in the design of potent inhibitors of histone lysine methyltransferases, J Mol Biol, 400, 1, 10.1016/j.jmb.2010.04.048 Liu, 2010, Protein lysine methyltransferase G9a inhibitors: design, synthesis, and structure activity relationships of 2,4-diamino-7-aminoalkoxy-quinazolines, J Med Chem, 53, 5844, 10.1021/jm100478y Vedadi, 2011, A chemical probe selectively inhibits G9a and GLP methyltransferase activity in cells, Nat Chem Biol, 7, 566, 10.1038/nchembio.599 Ferguson, 2011, Structural basis of substrate methylation and inhibition of SMYD2, Structure, 19, 1262, 10.1016/j.str.2011.06.011 Sack, 2011, Structural basis for CARM1 inhibition by indole and pyrazole inhibitors, Biochem J, 436, 331, 10.1042/BJ20102161 Daigle, 2011, Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor, Cancer Cell, 20, 53, 10.1016/j.ccr.2011.06.009 Greiner, 2005, Identification of a specific inhibitor of the histone methyltransferase SU(VAR)3-9, Nat Chem Biol, 1, 143, 10.1038/nchembio721 Smith, 2009, Chemical mechanisms of histone lysine and arginine modifications, Biochim Biophys Acta, 1789, 45, 10.1016/j.bbagrm.2008.06.005 Arrowsmith, 2012, Epigenetic protein families: a new frontier for drug discovery, Nat Rev Drug Discov, 11, 384, 10.1038/nrd3674 Hojfeldt, 2013, Histone lysine demethylases as targets for anticancer therapy, Nat Rev Drug Discov, 12, 917, 10.1038/nrd4154 Kooistra, 2012, Molecular mechanisms and potential functions of histone demethylases, Nat Rev Mol Cell Biol, 13, 297, 10.1038/nrm3327 Shi, 2004, Histone demethylation mediated by the nuclear amine oxidase homolog LSD1, Cell, 119, 941, 10.1016/j.cell.2004.12.012 Lee, 2005, An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation, Nature, 437, 432, 10.1038/nature04021 Shi, 2005, Regulation of LSD1 histone demethylase activity by its associated factors, Mol Cell, 19, 857, 10.1016/j.molcel.2005.08.027 Klose, 2006, JmjC-domain-containing proteins and histone demethylation, Nat Rev Genet, 7, 715, 10.1038/nrg1945 Kahl, 2006, Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence, Cancer Res, 66, 11341, 10.1158/0008-5472.CAN-06-1570 Heidenblad, 2008, Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors, BMC Med Genomics, 1, 3, 10.1186/1755-8794-1-3 Schulte, 2009, Lysine-specific demethylase 1 is strongly expressed in poorly differentiated neuroblastoma: implications for therapy, Cancer Res, 69, 2065, 10.1158/0008-5472.CAN-08-1735 Lim, 2010, Lysine-specific demethylase 1 (LSD1) is highly expressed in ER-negative breast cancers and a biomarker predicting aggressive biology, Carcinogenesis, 31, 512, 10.1093/carcin/bgp324 Hayami, 2011, Overexpression of LSD1 contributes to human carcinogenesis through chromatin regulation in various cancers, Int J Cancer, 128, 574, 10.1002/ijc.25349 Kauffman, 2011, Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer, Mol Carcinog, 50, 931, 10.1002/mc.20758 Schmidt, 2007, trans-2-Phenylcyclopropylamine is a mechanism-based inactivator of the histone demethylase LSD1, Biochemistry, 46, 4408, 10.1021/bi0618621 Ueda, 2009, Identification of cell-active lysine specific demethylase 1-selective inhibitors, J Am Chem Soc, 131, 17536, 10.1021/ja907055q Culhane, 2010, Comparative analysis of small molecules and histone substrate analogues as LSD1 lysine demethylase inhibitors, J Am Chem Soc, 132, 3164, 10.1021/ja909996p Mimasu, 2010, Structurally designed trans-2-phenylcyclopropylamine derivatives potently inhibit histone demethylase LSD1/KDM1, Biochemistry, 49, 6494, 10.1021/bi100299r Binda, 2010, Biochemical, structural, and biological evaluation of tranylcypromine derivatives as inhibitors of histone demethylases LSD1 and LSD2, J Am Chem Soc, 132, 6827, 10.1021/ja101557k Ogasawara, 2011, Synthesis and biological activity of optically active NCL-1, a lysine-specific demethylase 1 selective inhibitor, Bioorg Med Chem, 19, 3702, 10.1016/j.bmc.2010.12.024 Benelkebir, 2011, Enantioselective synthesis of tranylcypromine analogues as lysine demethylase (LSD1) inhibitors, Bioorg Med Chem, 19, 3709, 10.1016/j.bmc.2011.02.017 Willmann, 2012, Impairment of prostate cancer cell growth by a selective and reversible lysine-specific demethylase 1 inhibitor, Int J Cancer, 131, 2704, 10.1002/ijc.27555 Schmitt, 2013, Nonpeptidic propargylamines as inhibitors of lysine specific demethylase 1 (LSD1) with cellular activity, J Med Chem, 56, 7334, 10.1021/jm400792m Vianello, 2014, Synthesis, biological activity and mechanistic insights of 1-substituted cyclopropylamine derivatives: a novel class of irreversible inhibitors of histone demethylase KDM1A, Eur J Med Chem, 86, 352, 10.1016/j.ejmech.2014.08.068 Pieroni, 2015, Further insights into the SAR of alpha-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A, Eur J Med Chem, 92, 377, 10.1016/j.ejmech.2014.12.032 Schenk, 2012, Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia, Nat Med, 18, 605, 10.1038/nm.2661 Fiskus, 2014, Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells, Leukemia, 28, 2155, 10.1038/leu.2014.119 Tsukada, 2006, Histone demethylation by a family of JmjC domain-containing proteins, Nature, 439, 811, 10.1038/nature04433 Rose, 2008, Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases, J Med Chem, 51, 7053, 10.1021/jm800936s King, 2010, Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors, PLoS One, 5, 10.1371/journal.pone.0015535 Luo, 2011, A selective inhibitor and probe of the cellular functions of Jumonji C domain-containing histone demethylases, J Am Chem Soc, 133, 9451, 10.1021/ja201597b Chang, 2011, Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds, ChemMedChem, 6, 759, 10.1002/cmdc.201100026 Zeng, 2005, Selective small molecules blocking HIV-1 Tat and coactivator PCAF association, J Am Chem Soc, 127, 2376, 10.1021/ja044885g Pan, 2007, Structure-guided optimization of small molecules inhibiting human immunodeficiency virus 1 Tat association with the human coactivator p300/CREB binding protein-associated factor, J Med Chem, 50, 2285, 10.1021/jm070014g Borah, 2011, A small molecule binding to the coactivator CREB-binding protein blocks apoptosis in cardiomyocytes, Chem Biol, 18, 531, 10.1016/j.chembiol.2010.12.021 Chung, 2011, Discovery and characterization of small molecule inhibitors of the BET family bromodomains, J Med Chem, 54, 3827, 10.1021/jm200108t Hammitzsch, 2015, CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses, Proc Natl Acad Sci U S A, 112, 10768, 10.1073/pnas.1501956112 Hay, 2014, Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains, J Am Chem Soc, 136, 9308, 10.1021/ja412434f Nicodeme, 2010, Suppression of inflammation by a synthetic histone mimic, Nature, 468, 1119, 10.1038/nature09589 Filippakopoulos, 2010, Selective inhibition of BET bromodomains, Nature, 468, 1067, 10.1038/nature09504 Delmore, 2011, BET bromodomain inhibition as a therapeutic strategy to target c-Myc, Cell, 146, 904, 10.1016/j.cell.2011.08.017 Shimamura, 2013, Efficacy of BET bromodomain inhibition in Kras-mutant non-small cell lung cancer, Clin Cancer Res, 19, 6183, 10.1158/1078-0432.CCR-12-3904 Henssen, 2013, BET bromodomain protein inhibition is a therapeutic option for medulloblastoma, Oncotarget, 4, 2080, 10.18632/oncotarget.1534 Bandopadhayay, 2014, BET bromodomain inhibition of MYC-amplified medulloblastoma, Clin Cancer Res, 20, 912, 10.1158/1078-0432.CCR-13-2281 Venkataraman, 2014, Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma, Oncotarget, 5, 2355, 10.18632/oncotarget.1659 Mertz, 2011, Targeting MYC dependence in cancer by inhibiting BET bromodomains, Proc Natl Acad Sci U S A, 108, 16669, 10.1073/pnas.1108190108 Herrmann, 2012, Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia AML, Oncotarget, 3, 1588, 10.18632/oncotarget.733 Dawson, 2011, Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia, Nature, 478, 529, 10.1038/nature10509 Fong, 2015, BET inhibitor resistance emerges from leukaemia stem cells, Nature, 525, 538, 10.1038/nature14888 Rathert, 2015, Transcriptional plasticity promotes primary and acquired resistance to BET inhibition, Nature, 525, 543, 10.1038/nature14898 Herold, 2011, Small-molecule ligands of methyl-lysine binding proteins, J Med Chem, 54, 2504, 10.1021/jm200045v James, 2013, Small-molecule ligands of methyl-lysine binding proteins: optimization of selectivity for L3MBTL3, J Med Chem, 56, 7358, 10.1021/jm400919p James, 2013, Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain, Nat Chem Biol, 9, 184, 10.1038/nchembio.1157 Harrison, 2013, Epigenetic drugs: new modulators of readers and erasers, Nat Rev Drug Discov, 12, 188, 10.1038/nrd3961 Knudson, 1971, Mutation and cancer: statistical study of retinoblastoma, Proc Natl Acad Sci U S A, 68, 820, 10.1073/pnas.68.4.820 Jiang, 2009, Aberrant DNA methylation is a dominant mechanism in MDS progression to AML, Blood, 113, 1315, 10.1182/blood-2008-06-163246 Cancer Genome Atlas Research N, 2013, Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia, N Engl J Med, 368, 2059, 10.1056/NEJMoa1301689 Challen, 2012, Dnmt3a is essential for hematopoietic stem cell differentiation, Nat Genet, 44, 23, 10.1038/ng.1009 Corces-Zimmerman, 2014, Preleukemic mutations in human acute myeloid leukemia affect epigenetic regulators and persist in remission, Proc Natl Acad Sci U S A, 111, 2548, 10.1073/pnas.1324297111 Shlush, 2014, Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia, Nature, 506, 328, 10.1038/nature13038 Jeong, 2014, Large conserved domains of low DNA methylation maintained by Dnmt3a, Nat Genet, 46, 17, 10.1038/ng.2836 Ley, 2010, DNMT3A mutations in acute myeloid leukemia, N Engl J Med, 363, 2424, 10.1056/NEJMoa1005143 Walter, 2011, Recurrent DNMT3A mutations in patients with myelodysplastic syndromes, Leukemia, 25, 1153, 10.1038/leu.2011.44 Figueroa, 2010, Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation, Cancer Cell, 18, 553, 10.1016/j.ccr.2010.11.015 Kosmider, 2009, TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs), Blood, 114, 3285, 10.1182/blood-2009-04-215814 Abdel-Wahab, 2009, Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies, Blood, 114, 144, 10.1182/blood-2009-03-210039 Dang, 2009, Cancer-associated IDH1 mutations produce 2-hydroxyglutarate, Nature, 462, 739, 10.1038/nature08617 Gross, 2010, Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations, J Exp Med, 207, 339, 10.1084/jem.20092506 Ward, 2010, The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate, Cancer Cell, 17, 225, 10.1016/j.ccr.2010.01.020 Ward, 2012, Identification of additional IDH mutations associated with oncometabolite R(−)-2-hydroxyglutarate production, Oncogene, 31, 2491, 10.1038/onc.2011.416 Xu, 2011, Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases, Cancer Cell, 19, 17, 10.1016/j.ccr.2010.12.014 Marcucci, 2010, IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study, J Clin Oncol, 28, 2348, 10.1200/JCO.2009.27.3730 Paschka, 2010, IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication, J Clin Oncol, 28, 3636, 10.1200/JCO.2010.28.3762 Patel, 2011, Acute myeloid leukemia with IDH1 or IDH2 mutation: frequency and clinicopathologic features, Am J Clin Pathol, 135, 35, 10.1309/AJCPD7NR2RMNQDVF Rohle, 2013, An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells, Science, 340, 626, 10.1126/science.1236062 de Botton S PD, Stein EM, DiNardo C, Fathi AT, Roboz GJ, et al., editor Clinical safety and activity of AG-120, a first-in-class potent inhibitor of the IDH1 mutant protein, in a phase I study of patients with advanced, IDH1-mutant hematological malignancies. 20th Congress of the European Hematology Association; 2015; Vienna, Austria2015. DiNardo C SE, Altman JK, Collins R, DeAngelo DJ, Fathi AT, et al., editor AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant enzyme, induced durable responses in a phase I study of IDH2 mutation-positive advanced hematologic malignancies. 20th Congress of the European Hematology Association; 2015; Vienna, Austria 2015. Shen, 2010, DNA methylation predicts survival and response to therapy in patients with myelodysplastic syndromes, J Clin Oncol, 28, 605, 10.1200/JCO.2009.23.4781 Figueroa, 2010, DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia, Cancer Cell, 17, 13, 10.1016/j.ccr.2009.11.020 Bullinger, 2010, Quantitative DNA methylation predicts survival in adult acute myeloid leukemia, Blood, 115, 636, 10.1182/blood-2009-03-211003 Qu, 2014, Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes, Epigenetics, 9, 1108, 10.4161/epi.29315 Delhommeau, 2009, Mutation in TET2 in myeloid cancers, N Engl J Med, 360, 2289, 10.1056/NEJMoa0810069 Tefferi, 2009, Detection of mutant TET2 in myeloid malignancies other than myeloproliferative neoplasms: CMML, MDS, MDS/MPN and AML, Leukemia, 23, 1343, 10.1038/leu.2009.59 Jones, 2007, The epigenomics of cancer, Cell, 128, 683, 10.1016/j.cell.2007.01.029 Sonnet, 2014, Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia, Genome Med, 6, 34, 10.1186/gm551 Fenaux, 2009, Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study, Lancet Oncol, 10, 223, 10.1016/S1470-2045(09)70003-8 Kantarjian, 2006, Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study, Cancer, 106, 1794, 10.1002/cncr.21792 Quintas-Cardama, 2010, Therapy with azanucleosides for myelodysplastic syndromes, Nat Rev Clin Oncol, 7, 433, 10.1038/nrclinonc.2010.87 Taylor, 1982, Mechanism of action of eukaryotic DNA methyltransferase. Use of 5-azacytosine-containing DNA, J Mol Biol, 162, 679, 10.1016/0022-2836(82)90395-3 Weisenberger, 2004, Role of the DNA methyltransferase variant DNMT3b3 in DNA methylation, Mol Cancer Res, 2, 62, 10.1158/1541-7786.62.2.1 Jones, 1980, Cellular differentiation, cytidine analogs and DNA methylation, Cell, 20, 85, 10.1016/0092-8674(80)90237-8 Creusot, 1982, Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2′-deoxycytidine, J Biol Chem, 257, 2041, 10.1016/S0021-9258(19)68144-5 Christman, 1983, Effect of 5-azacytidine on differentiation and DNA methylation in human promyelocytic leukemia cells (HL-60), Cancer Res, 43, 763 Liu, 2007, Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC–MS/MS method, Nucleic Acids Res, 35, 10.1093/nar/gkl1156 Griffiths, 2008, DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes, Semin Hematol, 45, 23, 10.1053/j.seminhematol.2007.11.007 Fandy, 2009, Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies, Blood, 114, 2764, 10.1182/blood-2009-02-203547 Qin, 2011, Mechanisms of resistance to decitabine in the myelodysplastic syndrome, PLoS One, 6, 10.1371/journal.pone.0023372 Klco, 2013, Genomic impact of transient low-dose decitabine treatment on primary AML cells, Blood, 121, 1633, 10.1182/blood-2012-09-459313 Meldi, 2015, Specific molecular signatures predict decitabine response in chronic myelomonocytic leukemia, J Clin Invest, 125, 1857, 10.1172/JCI78752 Akalin, 2012, Base-pair resolution DNA methylation sequencing reveals profoundly divergent epigenetic landscapes in acute myeloid leukemia, PLoS Genet, 8, 10.1371/journal.pgen.1002781 Gore, 2006, Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms, Cancer Res, 66, 6361, 10.1158/0008-5472.CAN-06-0080 Daskalakis, 2002, Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-aza-2′-deoxycytidine (decitabine) treatment, Blood, 100, 2957, 10.1182/blood.V100.8.2957 Galm, 2005, Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia, Ann Hematol, 84, 39, 10.1007/s00277-005-0005-0 Esteller, 2001, A gene hypermethylation profile of human cancer, Cancer Res, 61, 3225 Schermelleh, 2005, Trapped in action: direct visualization of DNA methyltransferase activity in living cells, Nat Methods, 2, 751, 10.1038/nmeth794 Santi, 1984, Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine, Proc Natl Acad Sci U S A, 81, 6993, 10.1073/pnas.81.22.6993 Gabbara, 1995, The mechanism of inhibition of DNA (cytosine-5-)-methyltransferases by 5-azacytosine is likely to involve methyl transfer to the inhibitor, Biochem J, 307, 87, 10.1042/bj3070087 Ferguson, 1997, Role of estrogen receptor gene demethylation and DNA methyltransferase. DNA adduct formation in 5-aza-2′deoxycytidine-induced cytotoxicity in human breast cancer cells, J Biol Chem, 272, 32260, 10.1074/jbc.272.51.32260 Palii, 2008, 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, 28, 752, 10.1128/MCB.01799-07 Hollenbach, 2010, A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines, PLoS One, 5, 10.1371/journal.pone.0009001 Issa, 2004, Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies, Blood, 103, 1635, 10.1182/blood-2003-03-0687 Tsai, 2012, Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells, Cancer Cell, 21, 430, 10.1016/j.ccr.2011.12.029 Karpf, 2006, A potential role for epigenetic modulatory drugs in the enhancement of cancer/germ-line antigen vaccine efficacy, Epigenetics, 1, 116, 10.4161/epi.1.3.2988 Natsume, 2008, The DNA demethylating agent 5-aza-2′-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma, Int J Cancer, 122, 2542, 10.1002/ijc.23407 Almstedt, 2010, The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells, Leuk Res, 34, 899, 10.1016/j.leukres.2010.02.004 Bao, 2011, MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells to facilitate cytotoxic T lymphocyte-mediated tumor cell killing, Cancer Immunol Immunother, 60, 1299, 10.1007/s00262-011-1037-z Yang, 2012, Decitabine and vorinostat cooperate to sensitize colon carcinoma cells to Fas ligand-induced apoptosis in vitro and tumor suppression in vivo, J Immunol, 188, 4441, 10.4049/jimmunol.1103035 Konkankit, 2011, Decitabine immunosensitizes human gliomas to NY-ESO-1 specific T lymphocyte targeting through the Fas/Fas ligand pathway, J Transl Med, 9, 192, 10.1186/1479-5876-9-192 Yee, 2002, Modulating T-cell immunity to tumours: new strategies for monitoring T-cell responses, Nat Rev Cancer, 2, 409, 10.1038/nrc820 De Smet, 1996, The activation of human gene MAGE-1 in tumor cells is correlated with genome-wide demethylation, Proc Natl Acad Sci U S A, 93, 7149, 10.1073/pnas.93.14.7149 De Smet, 1999, DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter, Mol Cell Biol, 19, 7327, 10.1128/MCB.19.11.7327 Woloszynska-Read, 2008, Intertumor and intratumor NY-ESO-1 expression heterogeneity is associated with promoter-specific and global DNA methylation status in ovarian cancer, Clin Cancer Res, 14, 3283, 10.1158/1078-0432.CCR-07-5279 Srivastava, 2014, Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts, Leuk Res, 38, 1332, 10.1016/j.leukres.2014.09.001 Coral, 2013, Immunomodulatory activity of SGI-110, a 5-aza-2′-deoxycytidine-containing demethylating dinucleotide, Cancer Immunol Immunother, 62, 605, 10.1007/s00262-012-1365-7 Coral, 2006, Phenotypic and functional changes of human melanoma xenografts induced by DNA hypomethylation: immunotherapeutic implications, J Cell Physiol, 207, 58, 10.1002/jcp.20540 Navada, 2014, Clinical development of demethylating agents in hematology, J Clin Invest, 124, 40, 10.1172/JCI69739 Duvic, 2007, Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL), Blood, 109, 31, 10.1182/blood-2006-06-025999 San-Miguel, 2014, Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial, Lancet Oncol, 15, 1195, 10.1016/S1470-2045(14)70440-1 Cameron, 1999, Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer, Nat Genet, 21, 103, 10.1038/5047 Gore, 2005, Combination therapy with DNA methyltransferase inhibitors in hematologic malignancies, Nat Clin Pract Oncol, 2, S30, 10.1038/ncponc0346 Prebet, 2014, Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US Leukemia Intergroup trial E1905, J Clin Oncol, 32, 1242, 10.1200/JCO.2013.50.3102 Fang, 2014, The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer, Clin Cancer Res, 20, 6504, 10.1158/1078-0432.CCR-14-1553 Kuang, 2015, Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin, Mol Oncol, 9, 1799, 10.1016/j.molonc.2015.06.002 Leshchenko, 2015, Harnessing Noxa demethylation to overcome Bortezomib resistance in mantle cell lymphoma, Oncotarget, 6, 27332, 10.18632/oncotarget.2903 Xia, 2014, Treatment of resistant metastatic melanoma using sequential epigenetic therapy (decitabine and panobinostat) combined with chemotherapy (temozolomide), Cancer Chemother Pharmacol, 74, 691, 10.1007/s00280-014-2501-1 Vendetti, 2015, Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer, Oncotarget, 6, 56, 10.18632/oncotarget.2695 Benson, 2015, Carboplatin with decitabine therapy, in recurrent platinum resistant ovarian cancer, alters circulating miRNAs concentrations: a pilot study, PLoS One, 10, 10.1371/journal.pone.0141279 Scandura, 2011, Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML, Blood, 118, 1472, 10.1182/blood-2010-11-320093 Attman, 2015, Etiology, clinical course and outcome of healthcare-associated bloodstream infections in patients with hematological malignancies: a retrospective study of 350 patients in a Finnish tertiary care hospital, Leuk Lymphoma, 1–8 Ranganathan, 2015, Decitabine priming enhances the antileukemic effects of exportin 1 (XPO1) selective inhibitor selinexor in acute myeloid leukemia, Blood, 125, 2689, 10.1182/blood-2014-10-607648 Clozel, 2013, Mechanism-based epigenetic chemosensitization therapy of diffuse large B-cell lymphoma, Cancer Discov, 3, 1002, 10.1158/2159-8290.CD-13-0117 Odunsi, 2007, Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer, Proc Natl Acad Sci U S A, 104, 12837, 10.1073/pnas.0703342104 Odunsi, 2014, Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer, Cancer Immunol Res, 2, 37, 10.1158/2326-6066.CIR-13-0126 Wang, 2015, Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model, Cancer Immunol Res, 3, 1030, 10.1158/2326-6066.CIR-15-0073 Wrangle, 2013, Alterations of immune response of non-small cell lung cancer with azacytidine, Oncotarget, 4, 2067, 10.18632/oncotarget.1542