The future of epigenetic therapy in solid tumours - Lessons from the past

Nature Reviews Clinical Oncology

Volumn 10, Issue 5, 2013, Pages 256-266

  Azad, Nilofer ^a   Zahnow, Cynthia A ^a   Rudin, Charles M ^a   Baylin, Stephen B ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

5 AZA 2' DEOXYCYTIDINE; AZACITIDINE; CARBOPLATIN; ENTINOSTAT; ERLOTINIB; EXEMESTANE; HISTONE DEACETYLASE INHIBITOR; PACLITAXEL; PEMETREXED; PLACEBO; ROMIDEPSIN; TRICHOSTATIN A; VORINOSTAT;

ACUTE GRANULOCYTIC LEUKEMIA; BREAST CANCER; CANCER RESISTANCE; COLORECTAL CANCER; CPG ISLAND; CUTANEOUS T CELL LYMPHOMA; DNA METHYLATION; DRUG CYTOTOXICITY; EPIGENETICS; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; GENE EXPRESSION REGULATION; GENE MUTATION; HISTONE ACETYLATION; HUMAN; LOW DRUG DOSE; LUNG NON SMALL CELL CANCER; MULTIPLE CYCLE TREATMENT; MYELODYSPLASTIC SYNDROME; OVARY CANCER; OVERALL SURVIVAL; PERIPHERAL T CELL LYMPHOMA; PLURIPOTENT STEM CELL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; REVIEW; SOLID TUMOR; TUMOR SUPPRESSOR GENE;

ANIMALS; ANTINEOPLASTIC AGENTS; CLINICAL TRIALS AS TOPIC; COMBINED MODALITY THERAPY; DNA (CYTOSINE-5-)-METHYLTRANSFERASE; DNA METHYLATION; DNA, NEOPLASM; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; DRUG SCREENING ASSAYS, ANTITUMOR; DRUG THERAPY, COMBINATION; ENZYME INHIBITORS; EPIGENESIS, GENETIC; FORECASTING; GENETIC THERAPY; HEMATOLOGIC NEOPLASMS; HISTONE DEACETYLASE INHIBITORS; HUMANS; MOLECULAR TARGETED THERAPY; MULTICENTER STUDIES AS TOPIC; MYELODYSPLASTIC SYNDROMES; NEOPLASMS; PROMOTER REGIONS, GENETIC;

EID: 84877574817     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2013.42     Document Type: Review

References (126)

1. Jones, P., A.Baylin, S., B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415-428 (2002
2. Jones, P., A.Baylin, S., B. The epigenomics of, cancer. Cell 128, 683-692 (2007
3. Ecker, J., R.et al.Genomics: ENCODE explained. Nature 489, 52-55 (2012
4. Holliday, R. DNA methylation and epigenetic mechanisms. Cell Biophys. 15, 15-20 (1989
5. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693-705 (2007
6. Caparros, M. (Ed.) Epigenetics (Cold Spring Harbor Laboratory Press, 2007
7. Allis, C., D., Jenuwein, T.Reinberg, D. (Eds) Epigenetics (Cold Spring Harbor Laboratory Press, 2007
8. van der Vlag, J.Otte, A., P. Transcriptional repression mediated by the human polycomb-group protein EED involves histone deacetylation. Nat. Genet. 23, 474-478 (1999
9. Ley, T., J.et al.DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 363, 2424-2433 (2010
10. Thol, F.et al.Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J. Clin. Oncol. 29, 2889-2896 (2011
11. Metzeler, K., H.et al.TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia; A Cancer and Leukemia Group B study. J. Clin. Oncol. 29, 1373-1381 (2011
12. Bejar, R.et al.Clinical effect of point mutations in myelodysplastic syndromes. N. Engl. J. Med. 364, 2496-2506 (2011
13. Abdel-WahabO. et al. Concomitant analysis of, EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms Leukemia 25, 1200-1202 (2011
14. Metzeler, K., H.et al.ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN favorable genetic category. Blood 118, 6920-6929 (2011
15. Guglielmelli, P.et al.EZH2 mutational status predicts poor survival in myelofibrosis. Blood 118, 5227-5234 (2011
16. TefferiA.et al. TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis Leukemia 23, 905-911 (2009
17. Tefferi, A.et al.IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: Clinical evidence for leukemogenic collaboration with JAK2V617F. Leukemia 26, 475-480 (2012
18. TefferiA.et al. IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis Leukemia 24, 1302-1309 (2010
19. De Carvalho, D., D.et al.DNA methylation screening identifies driver epigenetic events of, cancer cell survival. Cancer Cell 21, 655-667 (2012
20. Baylin, S., B.Jones, P., A. A decade of exploring the cancer epigenome - biological and translational implications. Nat. Rev. Cancer 11, 726-734 (2011
21. McCabe, M., T.et al.EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 492, 108-112 (2012
22. Berdasco, M.Esteller, M. Genetic syndromes caused by mutations in epigenetic genes. Hum., Genet. 132, 359-383 (2013
23. Shih, A., H., Abdel-Wahab, O., Patel, J., P. &, Levine, R., L. The role of mutations in epigenetic regulators in myeloid malignancies. Nat. Rev. Cancer 12, 599-612 (2012
24. Kaminskas, E.et al.Approval summary; Azacitidine for treatment of myelodysplastic syndrome subtypes. Clin. Cancer Res. 11, 3604-3608 (2005
25. Silverman, L., R.et al.Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome; A study of the cancer, and leukemia group B. J. Clin. Oncol. 20, 2429-2440 (2002
26. Kaminskas, E., Farrell, A., T., Wang, Y., C., Sridhara, R.Pazdur, R. FDA drug approval summary; Azacitidine (5-azacytidine, Vidaza) for injectable suspension. Oncologist 10, 176-182 (2005
27. Kantarjian, H.et al.Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase, III randomized study. Cancer 106, 1794-1803 (2006
28. Piekarz, R., L.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. 27, 5410-5417 (2009
29. Whittaker, S., J.et al.Final results from a, multicenter, international, pivotal study of, romidepsin in refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 28, 4485-4491 (2010
30. O'Connor, O., A.et al.Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J. Clin. Oncol. 24, 166-173 (2006
31. Duvic, M.et al.Phase, 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL.). Blood 109, 31-39 (2007
32. Issa, J., P. Optimizing therapy with methylation inhibitors in myelodysplastic syndromes: Dose, duration, and patient selection. Nat. Clin. Pract. Oncol. 2 (Suppl. 1), S24-29 (2005
33. Herman, J., G.Baylin, S., B. Gene silencing in, cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042-2054 (2003
34. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148-1159 (2008
35. Doi, A.et al.Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat., Genet. 41, 1350-1353 (2009
36. Lane, A., A.Chabner, B., A. Histone deacetylase inhibitors in cancer therapy. J. Clin. Oncol. 27, 5459-5468 (2009
37. Popovic, R.Licht, J., D. Emerging epigenetic targets and therapies in cancer medicine. Cancer Discov. 2, 405-413 (2012
38. Dawson, M., A.Kouzarides, T. Cancer epigenetics: From mechanism to therapy. Cell 150, 12-27 (2012
39. Ohm, J., E.et al.A stem cell-like chromatin pattern may predispose tumor suppressor genes to DNA hypermethylation and heritable silencing. Nat. Genet. 39, 237-242 (2007
40. Widschwendter, M.et al.Epigenetic stem cell signature in cancer. Nat. Genet. 39, 157-158 (2007
41. Schlesinger, Y.et al.Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de, novo methylation in cancer. Nat. Genet. 39, 232-236 (2007
42. Kelly, T., K., De Carvalho, D., D.Jones, P., A. Epigenetic modifications as therapeutic targets. Nat. Biotechnol. 28, 1069-1078 (2010
43. Issa, J., P.Kantarjian, H., M. Introduction: Emerging role of epigenetic therapy: Focus on decitabine. Semin. Hematol. 42 (Suppl.), S1-S2 (2005
44. Egger, G., Liang, G., Aparicio, A.Jones, P., A. Epigenetics in human disease and prospects for epigenetic therapy. Nature 429, 457-463 (2004
45. Hochedlinger, K.Plath, K. Epigenetic reprogramming and induced pluripotency. Development 136, 509-523 (2009
46. Lister, R.et al.Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471, 68-73 (2011
47. Feng, B., Ng, J., H., Heng, J., C.Ng, H., H. Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell 4, 301-312 (2009
48. Hanahan, D.Weinberg, R., A. The hallmarks of, cancer. Cell 100, 57-70 (2000
49. Hanahan, D.Weinberg, R., A. Hallmarks of cancer: The next generation. Cell 144, 646-674 (2011
50. Morey, L.et al.Nonoverlapping functions of the Polycomb group Cbx family of proteins in embryonic stem cells. Cell Stem Cell 10, 47-62 (2012
51. Easwaran, H.et al.A DNA hypermethylation module for the stem/progenitor cell signature of, cancer. Genome Res. 22, 837-849 (2012
52. Paez, J., G.et al.EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304, 1497-1500 (2004
53. Tsao, M., S.et al.Erlotinib in lung cancer - molecular and clinical predictors of outcome. N., Engl. J. Med. 353, 133-144 (2005
54. Nahta, R., Yu, D., Hung., M., C., Hortobagyi, G., N.Esteva, F., J. Mechanisms of disease: Understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol. 3, 269-280 (2006
55. Astsaturov, I.et al.Synthetic lethal screen of an, EGFR-centered network to improve targeted therapies. Sci. Signal. 3, ra67 (2010
56. Poulikakos, P., I.Rosen, N. Mutant BRAF melanomas- -dependence and resistance. Cancer Cell 19, 11-15 (2011
57. Solit, D., B.Rosen, N. Resistance to BRAF inhibition in melanomas. N. Engl. J. Med. 364, 772-774 (2011
58. Soda, M.et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566 (2007
59. Sorm, F.Vesely, J. Effect of 5-aza-2'-deoxycytidine against leukemic and hemopoietic tissues in AKR mice. Neoplasma 15, 339-343 (1968
60. Notari, R., E.DeYoung, J., L. Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions. J. Pharm. Sci. 64, 1148-1157 (1975
61. Jones, P., A.Taylor, S., M. Cellular differentiation, cytidine analogs and DNA methylation. Cell 20, 85-93 (1980
62. Juergens, R., A.et al.Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer. Cancer Discov. 1, 598-607 (2011
63. Ferguson, A., T.et al.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, 32260-32266 (1997
64. Gabbara, S.Bhagwat, A., S. The mechanism of inhibition of DNA (cytosine-5-)-methyltransferases by 5-azacytosine is likely to involve methyl transfer to the inhibitor. Biochem. J. 307, 87-92 (1995
65. Santi, D., V., Norment, A.Garrett, C., E. Covalent, bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine. Proc. Natl Acad. Sci. USA 81, 6993-6997 (1984
66. Ghoshal, K.et al.5-Aza-deoxycytidine induces selective degradation of DNA methyltransferase 1, by a proteasomal pathway that requires the KEN box, bromo-adjacent homology domain, and nuclear localization signal. Mol. Cell Biol. 25, 4727-4741 (2005
67. Tsai, H., C.et al.Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21, 430-446 (2012
68. Sharma, S., V.et al.A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69-80 (2010
69. Silverman, L., R.et al.Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher-risk myelodysplastic syndromes. Cancer 117, 2697-2702 (2011
70. Fandy, T., E.et al.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, 2764-2773 (2009
71. Brock, M., V.et al.DNA methylation markers and early recurrence in stage I lung cancer. N. Engl. J. Med. 358, 1118-1128 (2008
72. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330-337 (2012
73. Hammerman, P., S.et al.Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519-525 (2012
74. Koboldt, D., C.et al.Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70 (2012
75. Saito, Y.et al.Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell 9, 435-443 (2006
76. You, J., S.Jones, P., A. Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell 22, 9-20 (2012
77. Noushmehr, H.et al.Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17, 510-522 (2010
78. Suter, C., M., Martin, D., I.Ward, R., L. Germline epimutation of MLH1 in individuals with multiple cancers. Nat. Genet. 36, 497-501 (2004
79. Chan, E., C., Lam, S., Y., Fu, K., H.Kwong, Y., L. Polymorphisms of the GSTM1, GSTP1, MPO, XRCC1, and NQO1 genes in Chinese patients with non-small cell lung cancers: Relationship with aberrant promoter methylation of the CDKN2A and RARB genes. Cancer Genet. Cytogenet. 162, 10-20 (2005
80. Chan, T., L.et al.Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer. Nat. Genet. 38, 1178-1183 (2006
81. Ligtenberg, M., J.et al.Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1. Nat. Genet. 41, 112-117 (2009
82. Girard, N.et al.Third-line chemotherapy in advanced non-small cell lung cancer: Identifying the candidates for routine practice. J. Thorac. Oncol. 4, 1544-1549 (2009
83. Humeniuk, R.et al.Decreased levels of UMP kinase as a mechanism of fluoropyrimidine resistance. Mol. Cancer Ther. 8, 1037-1044 (2009
84. Meng, F., Sun, G., Zhong, M., Yu, Y. &, Brewer, M., A. Anticancer efficacy of cisplatin and trichostatin A or 5-aza-2'-deoxycytidine on ovarian cancer. Br. J. Cancer 108, 579-586 (2013
85. Bhatla, T.et al.Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood 119, 5201-5210 (2012
86. Shakya, R.et al.Hypomethylating therapy in an, aggressive stroma-rich model of pancreatic carcinoma. Cancer Res. 73, 885-896 (2012
87. FuS.et al. Phase, 1b-2a study to reverse platinum resistance through use of a hypomethylating agent, azacitidine, in patients with platinum-resistant or platinum-refractory epithelial ovarian cancer Cancer 117, 1661-1669 (2011
88. Matei, D.et al.Epigenetic resensitization to, platinum in ovarian cancer. Cancer Res. 72, 2197-2205 (2012
89. Gray, S., G.Ekström, T., J. The human histone deacetylase family. Exp. Cell Res. 262, 75-83 (2001
90. Solomon, J., M.et al.Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell Biol. 26, 28-38 (2006
91. O'Hagan, H., M., Mohammad, H., P.Baylin, S., B. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet. 4, e1000155 (2008
92. Vaquero, A.et al.SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20, 1256-1261 (2006
93. Pruitt, K.et al.Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006
94. Pediconi, N.et al.hSirT1-dependent regulation of, the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage. Mol. Cell Biol. 29, 1989-1998 (2009
95. Cooper, S., J.et al.Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of, combined HDAC and methyltransferase inhibitors in chemoresistant cancers. Mol. Cancer Ther. 11, 2105-2115 (2012
96. Isozaki, Y.et al.Identification of novel molecular targets regulated by tumor suppressive miR-375 induced by histone acetylation in esophageal squamous cell carcinoma. Int. J. Oncol. 41, 985-994 (2012
97. Shin, H., Lee, Y., S.Lee, Y., C. Sodium butyrate-induced DAPK-mediated apoptosis in human gastric cancer cells. Oncol. Rep. 27, 1111-1115 (2012
98. Mund, C.Lyko, F. Epigenetic cancer therapy: Proof of concept and remaining challenges. Bioessays 32, 949-957 (2010
99. Verbrugge, I., Johnstone, R., W.Bots, M. Promises and challenges of anticancer drugs that target the epigenome. Epigenomics 3, 547-565 (2011
100. Robert, C.Rassool, F., V. HDAC inhibitors: Roles of DNA damage and repair. Adv. Cancer Res. 116, 87-129 (2012
101. Kachhap, S., K.et al.Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS ONE 5, e11208 (2010
102. Gilbertson, R., J.Graham, T., A. Cancer: Resolving the stem-cell debate. Nature 488, 462-463 (2012
103. Chen, J.et al.A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522-526 (2012
104. Driessens, G., Beck, B., Caauwe, A., Simons, B., D.Blanpain, C. Defining the mode of tumour growth by clonal analysis. Nature 488, 527-530 (2012
105. Schepers, A., G.et al.Lineage tracing reveals, Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337, 730-735 (2012
106. Villanueva, J.et al.Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683-695 (2010
107. Yeo, W.et al.Epigenetic therapy using belinostat for patients with unresectable hepatocellular carcinoma; A multicenter phase, I/II study with biomarker and pharmacokinetic analysis of tumors from patients in the Mayo Phase, II Consortium and the Cancer Therapeutics Research Group. J. Clin. Oncol. 30, 3361-3367 (2012
108. Hainsworth, J., D.et al.A phase, II trial of panobinostat, a histone deacetylase inhibitor, in, the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest. 29, 451-455 (2011
109. Giaccone, G.et al.Phase, II study of belinostat in, patients with recurrent or refractory advanced thymic epithelial tumors. J. Clin. Oncol. 29, 2052-2059 (2011
110. Iwamoto, F., M.et al.A phase, I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03. Neuro. Oncol. 13, 509-516 (2011
111. Mackay, H., J.et al.Phase, II trial of the histone, deacetylase inhibitor belinostat in, women with platinum resistant epithelial ovarian cancer and micropapillary (LMP) ovarian, tumours. Eur. J. Cancer 46, 1573-1579 (2010
112. Witta, S., E.et al.Randomized phase, II trial of, erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy. J. Clin. Oncol. 30, 2248-2255 (2012
113. Ramalingam, S., S.et al.Carboplatin and paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer. J. Clin. Oncol. 28, 56-62 (2010
114. Yardley, D., A., Ismail-Khan, R.Klein, P. Results of ENCORE 301, a randomized, phase, II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive (ER+) breast cancer progressing on a nonsteroidal aromatase inhibitor (AI) [abstract 268]. J. Clin. Oncol. 29 (Suppl. 27), 268 (2011
115. Brahmer, J., R.et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455-2465 (2012
116. Topalian, S., L.et al.Safety, activity, and immune orrelates of anti-PD-1 antibody in, cancer. N., Engl. J. Med. 366, 2443-2454 (2012
117. Issa, J., P.et al.Interim results from a randomized phase, 1-2 first-in-human (FIH) study, of PK/PD guided escalating doses of SGI-110, a, novel subcutaneous (SQ) second generation hypomethylating agent (HMA) in relapsed/refractory MDS and AML [abstract LB-214]. Cancer Res. 72 (Suppl. 1), LB-214 (2012
118. Garcia-Manero, G.et al.Phase, I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia. J. Clin. Oncol. 29, 2521-2527 (2011
119. Chung, C., W.et al.Discovery and characterization of small molecule inhibitors of, the BET family bromodomains. J. Med. Chem. 54, 3827-3838 (2011
120. Spannhoff, A., Hauser, A., T., Heinke, R., Sippl, W. &, Jung, M. The emerging therapeutic potential of, histone methyltransferase and demethylase inhibitors. ChemMedChem 4, 1568-1582 (2009
121. Bernt, K., M.et al.MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66-78 (2011
122. Daigle, S., R.et al.Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53-65 (2011
123. Olsen, E., A.et al.Phase, IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J. Clin. Oncol. 25, 3109-3115 (2007
124. Ooi, S. K.et al. DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of, DNA Nature 448, 714-717 (2007
125. Hashimoto, H., Vertino, P., M.Cheng, X. Molecular coupling of DNA methylation and histone methylation. Epigenomics 2, 657-669 (2010
126. KantarjianH.et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia Blood 109, 52-57 (2007