bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.35754/0234-5730-2021-66-2-263-279bloodjour-288Research ArticleОБЗОРЫREVIEWSРоль эпигенетических модификаций ДНК и гистонов в лечении онкогематологических заболеванийThe Role of epigenetic modifications of DNA and histones in the treatment of oncohematological diseaseshttps://orcid.org/0000-0002-0691-4079КарпенкоД. В.KarpenkoD. V.

Карпенко Дмитрий Владимирович, научный сотрудник лаборатории физиологии кроветворения

125167, Москва

Dmitriy V. Karpenko, Researcher, Laboratory of Hematopoietic Physiology

125167, Moscow

d_@list.ruhttps://orcid.org/0000-0001-6591-3183ПетинатиН. А.PetinatiN. A.

Петинати Наталия Арнольдовна, кандидат медицинских наук, старший научный сотрудник лаборатории физиологии кроветворения

125167, Москва

Natalia A. Petinati, Cand. Sci. (Med.), Senior Researcher, Laboratory of Hematopoietic Physiology

125167, Moscow

loel@mail.ruhttps://orcid.org/0000-0002-7150-0403ДризеН. И.DrizeN. J.

Дризе Нина Иосифовна, доктор биологических наук, профессор, заведующий лабораторией физиологии кроветворения

125167, Москва

Nina J. Drize, Dr. Sci. (Biol.), Professor, Head of the Laboratory of Hematopoietic Physiology

125167, Moscow

ndrize@yandex.ruhttps://orcid.org/0000-0003-0215-9085БигильдеевА. Е.BigildeevA. E.

Бигильдеев Алексей Евгеньевич, доктор биологических наук, ведущий научный сотрудник лаборатории физиологии кроветворения

125167, Москва

Aleksei E. Bigildeev, Dr. Sci. (Biol.), Leading Researcher, Laboratory of Hematopoietic Physiology

125167, Moscow

bigildeev.ae@gmail.comФГБУ «Национальный медицинский исследовательский центр гематологии» Министерства здравоохранения Российской ФедерацииРоссияNational Research Center for HematologyRussian Federation202102092021662263279Copyright © Карпенко Д.В., Петинати Н.А., Дризе Н.И., Бигильдеев А.Е., 20212021Карпенко Д.В., Петинати Н.А., Дризе Н.И., Бигильдеев А.Е.Karpenko D.V., Petinati N.A., Drize N.J., Bigildeev A.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/288Введение

Введение. Современные знания о биологии опухолевого процесса демонстрируют важность не только генетических нарушений, но и эпигенетических аномалий в опухолевых клетках. Исследование эпигенетики опухолей позволило получить представления о ключевых путях, связанных с онкогенезом и разработать новые эпигенетические методы лечения.

Цель обзора  — продемонстрировать важность эпигенетических изменений при гематологических заболеваниях и рассмотреть терапевтические подходы, направленные на эти механизмы.

Основные сведения

Основные сведения. Описываются наиболее изученные виды эпигенетических изменений в опухолевых клетках: метилирование цитозина в ДНК, метилирование и ацетилирование белков-гистонов. Рассматриваются ферменты, осуществляющие эти модификации, и  обсуждается их роль в  онкогенезе. Приводится описание лекарственных средств, направленных на изменение эпигенетического профиля клеток, в том числе гипометилирующих ДНК агентов, ингибиторов гистоновых деацетилаз и метилаз. Особое внимание уделено веществам, которые в настоящее время применяются для лечения гематологических заболеваний или находятся на разных стадиях клинических испытаний и в ближайшем будущем могут оказаться доступны для применения в клинической практике.

Introduction

Introduction. Current knowledge of tumour biology attests a dual genetic and epigenetic nature of cancer cell abnormalities. Tumour epigenetics research provided insights into the key pathways mediating oncogenesis and facilitated novel epigenetic therapies.

Aim — an overview of intricate involvement of epigenetic change in haematological morbidity and current therapeutic approaches to target the related mechanisms.

Main findings

Main findings. We review the best known epigenetic marks in tumour cells, e.g. DNA cytosine methylation, methylation and acetylation of histone proteins, the underlying enzymatic machinery and its role in oncogenesis. The epigenetic profile-changing drugs are described, including DNA hypomethylating agents, histone deacetylase and methylase inhibitors. A particular focus is made on substances currently approved in haematological therapy or undergoing clinical trial phases for future clinical availability.

эпигенетикаметилирование ДНКметилирование и ацетилирование белков-гистоновгематологиялейкозылимфомымиеломаepigeneticsDNA methylationmethylation and acetylation of histone proteinshematologyleukemialymphomasmyelomaReferencesJeffers V., Yang C., Huang S., et al. Bromodomains in protozoan parasites: Evolution, function, and opportunities for drug development. Microbiol Mol Biol Rev. 2017; 81(1). DOI: 10.1128/mmbr.00047-16.Jeffers V., Yang C., Huang S., et al. Bromodomains in protozoan parasites: Evolution, function, and opportunities for drug development. Microbiol Mol Biol Rev. 2017; 81(1). DOI: 10.1128/mmbr.00047-16.Sharif J., Muto M., Takebayashi S., et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007; 450(7171): 908–12. DOI: 10.1038/nature06397.Sharif J., Muto M., Takebayashi S., et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature. 2007; 450(7171): 908–12. DOI: 10.1038/nature06397.Cortellino S., Xu J., Sannai M., et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011; 146(1): 67–79. DOI: 10.1016/j.cell.2011.06.020.Cortellino S., Xu J., Sannai M., et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011; 146(1): 67–79. DOI: 10.1016/j.cell.2011.06.020.Genovese G., Kähler A.K., Handsaker R.E., et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26): 2477–87. DOI: 10.1056/NEJMoa1409405.Genovese G., Kähler A.K., Handsaker R.E., et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med. 2014; 371(26): 2477–87. DOI: 10.1056/NEJMoa1409405.Deaton A.M., Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011; 25(10): 1010–22. DOI: 10.1101/gad.2037511.Deaton A.M., Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011; 25(10): 1010–22. DOI: 10.1101/gad.2037511.Hashimoto K., Oreffo R.O.C., Gibson M.B., et al. DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum. 2009; 60(11): 3303–13. DOI: 10.1002/art.24882.Hashimoto K., Oreffo R.O.C., Gibson M.B., et al. DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes. Arthritis Rheum. 2009; 60(11): 3303–13. DOI: 10.1002/art.24882.Kinner A., Wu W., Staudt C., et al. Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 2008; 36(17): 5678–94. DOI: 10.1093/nar/gkn550.Kinner A., Wu W., Staudt C., et al. Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res. 2008; 36(17): 5678–94. DOI: 10.1093/nar/gkn550.https://www.thermofisher.com/ru/ru/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/antibody-methods/epigenetics/_jcr_content/MainParsys/image_353a/backgroundimg.img.jpg/1595366270303.jpghttps://www.thermofisher.com/ru/ru/home/life-science/antibodies/antibodies-learning-center/antibodies-resource-library/antibody-methods/epigenetics/_jcr_content/MainParsys/image_353a/backgroundimg.img.jpg/1595366270303.jpgHarikumar A., Meshorer E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 2015; 16(12): 1609–19. DOI: 10.15252/embr.201541011.Harikumar A., Meshorer E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 2015; 16(12): 1609–19. DOI: 10.15252/embr.201541011.Heintzman N.D., Stuart R.K., Hon G., et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007; 39(3): 311–8. DOI: 10.1038/ng1966.Heintzman N.D., Stuart R.K., Hon G., et al. Distinct and predictive chromatin signatures of transcriptional promoters and enhancers in the human genome. Nat Genet. 2007; 39(3): 311–8. DOI: 10.1038/ng1966.Kleff S., Andrulis E.D., Anderson C.W., et al. Identification of a gene encoding a yeast histone H4 acetyltransferase. J Biol Chem. 1995; 270(42): 24674–7. DOI: 10.1074/jbc.270.42.24674.Kleff S., Andrulis E.D., Anderson C.W., et al. Identification of a gene encoding a yeast histone H4 acetyltransferase. J Biol Chem. 1995; 270(42): 24674–7. DOI: 10.1074/jbc.270.42.24674.Sobulo O.M., Borrow J., Tomek R., et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16) (q23;p13.3). Proc Natl Acad Sci USA. 1997; 94(16): 8732–7. DOI: 10.1073/pnas.94.16.8732.Sobulo O.M., Borrow J., Tomek R., et al. MLL is fused to CBP, a histone acetyltransferase, in therapy-related acute myeloid leukemia with a t(11;16) (q23;p13.3). Proc Natl Acad Sci USA. 1997; 94(16): 8732–7. DOI: 10.1073/pnas.94.16.8732.Li B.E., Ernst P. Two decades of leukemia oncoprotein epistasis: The MLL1 paradigm for epigenetic deregulation in leukemia. Exp Hematol. 2014; 42(12): 995–1012. DOI: 10.1016/j.exphem.2014.09.006.Li B.E., Ernst P. Two decades of leukemia oncoprotein epistasis: The MLL1 paradigm for epigenetic deregulation in leukemia. Exp Hematol. 2014; 42(12): 995–1012. DOI: 10.1016/j.exphem.2014.09.006.Wang J., Iwasaki H., Krivtsov A., et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 2005; 24(2): 368–81. DOI: 10.1038/sj.emboj.7600521.Wang J., Iwasaki H., Krivtsov A., et al. Conditional MLL-CBP targets GMP and models therapy-related myeloproliferative disease. EMBO J. 2005; 24(2): 368–81. DOI: 10.1038/sj.emboj.7600521.Shima H., Yamagata K., Aikawa Y., et al. Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion. Int J Hematol. 2014; 99(1): 21–31. DOI: 10.1007/s12185-013-1466-x.Shima H., Yamagata K., Aikawa Y., et al. Bromodomain-PHD finger protein 1 is critical for leukemogenesis associated with MOZ–TIF2 fusion. Int J Hematol. 2014; 99(1): 21–31. DOI: 10.1007/s12185-013-1466-x.Pasqualucci L., Dominguez-Sola D., Chiarenza A., et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471(7337): 189–95. DOI: 10.1038/nature09730.Pasqualucci L., Dominguez-Sola D., Chiarenza A., et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011; 471(7337): 189–95. DOI: 10.1038/nature09730.Deguchi K., Ayton P.M., Carapeti M., et al. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell. 2003; 3(3): 259–71. DOI: 10.1016/S1535-6108(03)00051-5.Deguchi K., Ayton P.M., Carapeti M., et al. MOZ-TIF2-induced acute myeloid leukemia requires the MOZ nucleosome binding motif and TIF2-mediated recruitment of CBP. Cancer Cell. 2003; 3(3): 259–71. DOI: 10.1016/S1535-6108(03)00051-5.Samec M., Liskova A., Koklesova L., et al. Fluctuations of histone chemical modifications in breast, prostate, and colorectal cancer: An implication of phytochemicals as defenders of chromatin equilibrium. Biomolecules. 2019; 9(12): 829. DOI: 10.3390/biom9120829.Samec M., Liskova A., Koklesova L., et al. Fluctuations of histone chemical modifications in breast, prostate, and colorectal cancer: An implication of phytochemicals as defenders of chromatin equilibrium. Biomolecules. 2019; 9(12): 829. DOI: 10.3390/biom9120829.Choudhary C., Kumar C., Gnad F., et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009; 325(5942): 834–40. DOI: 10.1126/science.1175371.Choudhary C., Kumar C., Gnad F., et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 2009; 325(5942): 834–40. DOI: 10.1126/science.1175371.Morishima T., Krahl A.C., Nasri M., et al. LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis. Blood. 2019; 134(14): 1159–75. DOI: 10.1182/blood.2019000095.Morishima T., Krahl A.C., Nasri M., et al. LMO2 activation by deacetylation is indispensable for hematopoiesis and T-ALL leukemogenesis. Blood. 2019; 134(14): 1159–75. DOI: 10.1182/blood.2019000095.Zucchetti B., Shimada A.K., Katz A., et al. The role of histone deacetylase inhibitors in metastatic breast cancer. Breast. 2019; 43: 130–4. DOI: 10.1016/j.breast.2018.12.001.Zucchetti B., Shimada A.K., Katz A., et al. The role of histone deacetylase inhibitors in metastatic breast cancer. Breast. 2019; 43: 130–4. DOI: 10.1016/j.breast.2018.12.001.Gregoretti I.V., Lee Y.-M., Goodson H.V. Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis. J Mol Biol. 2004; 338(1): 17–31. DOI: 10.1016/j.jmb.2004.02.006.Gregoretti I.V., Lee Y.-M., Goodson H.V. Molecular evolution of the histone deacetylase family: Functional implications of phylogenetic analysis. J Mol Biol. 2004; 338(1): 17–31. DOI: 10.1016/j.jmb.2004.02.006.Johnstone R.W., Licht J.D. Histone deacetylase inhibitors in cancer therapy: Is transcription the primary target? Cancer Cell. 2003; 4(1): 13–8. DOI: 10.1016/s1535-6108(03)00165-x.Johnstone R.W., Licht J.D. Histone deacetylase inhibitors in cancer therapy: Is transcription the primary target? Cancer Cell. 2003; 4(1): 13–8. DOI: 10.1016/s1535-6108(03)00165-x.Licht J.D. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene. 2001; 20(40): 5660–79. DOI: 10.1038/sj.onc.1204593.Licht J.D. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene. 2001; 20(40): 5660–79. DOI: 10.1038/sj.onc.1204593.Yu K.R., Espinoza D.A., Wu C., et al. The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood. 2018; 131(11): 1195–1205. DOI: 10.1182/blood-2017-08-802033.Yu K.R., Espinoza D.A., Wu C., et al. The impact of aging on primate hematopoiesis as interrogated by clonal tracking. Blood. 2018; 131(11): 1195–1205. DOI: 10.1182/blood-2017-08-802033.Long J., Jia M.-Y., Fang W.-Y., et al. FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia. Blood. 2020; 135(17): 1472–83. DOI: 10.1182/blood.2019003538.Long J., Jia M.-Y., Fang W.-Y., et al. FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia. Blood. 2020; 135(17): 1472–83. DOI: 10.1182/blood.2019003538.Shi Y., Whetstine J.R. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007; 25(1): 1–14. DOI: 10.1016/j.molcel.2006.12.010.Shi Y., Whetstine J.R. Dynamic regulation of histone lysine methylation by demethylases. Mol Cell. 2007; 25(1): 1–14. DOI: 10.1016/j.molcel.2006.12.010.Arrowsmith C.H., Bountra C., Fish P.V, et al. Epigenetic protein families: A new frontier for drug discovery. Nat Rev Drug Discov. 2012; 11(5): 384–400. DOI: 10.1038/nrd3674.Arrowsmith C.H., Bountra C., Fish P.V, et al. Epigenetic protein families: A new frontier for drug discovery. Nat Rev Drug Discov. 2012; 11(5): 384–400. DOI: 10.1038/nrd3674.Guenther M.G., Levine S.S., Boyer L.A., et al. A chromatin landmark and transcription initiation at most promoters in human cells. Cell. 2007; 130(1): 77–88. DOI: 10.1016/j.cell.2007.05.042.Guenther M.G., Levine S.S., Boyer L.A., et al. A chromatin landmark and transcription initiation at most promoters in human cells. Cell. 2007; 130(1): 77–88. DOI: 10.1016/j.cell.2007.05.042.McCabe M.T., Creasy C.L. EZH2 as a potential target in cancer therapy. Epigenomics. 2014; 6(3): 341–51. DOI: 10.2217/epi.14.23.McCabe M.T., Creasy C.L. EZH2 as a potential target in cancer therapy. Epigenomics. 2014; 6(3): 341–51. DOI: 10.2217/epi.14.23.Bödör C., Grossmann V., Popov N., et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013; 122(18): 3165–8. DOI: 10.1182/blood-2013-04-496893.Bödör C., Grossmann V., Popov N., et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013; 122(18): 3165–8. DOI: 10.1182/blood-2013-04-496893.McCabe M.T., Graves A.P., Ganji G., et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci USA. 2012; 109(8): 2989–94. DOI: 10.1073/pnas.1116418109.McCabe M.T., Graves A.P., Ganji G., et al. Mutation of A677 in histone methyltransferase EZH2 in human B-cell lymphoma promotes hypertrimethylation of histone H3 on lysine 27 (H3K27). Proc Natl Acad Sci USA. 2012; 109(8): 2989–94. DOI: 10.1073/pnas.1116418109.van Galen J.C., Dukers D.F., Giroth C., et al. Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction. Eur J Immunol. 2004; 34(7): 1870–81. DOI: 10.1002/eji.200424985.van Galen J.C., Dukers D.F., Giroth C., et al. Distinct expression patterns of polycomb oncoproteins and their binding partners during the germinal center reaction. Eur J Immunol. 2004; 34(7): 1870–81. DOI: 10.1002/eji.200424985.Béguelin W., Popovic R., Teater M., et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5): 677–92. DOI: 10.1016/j.ccr.2013.04.011.Béguelin W., Popovic R., Teater M., et al. EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation. Cancer Cell. 2013; 23(5): 677–92. DOI: 10.1016/j.ccr.2013.04.011.Milne T.A., Briggs S.D., Brock H.W., et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002; 10(5): 1107–17. DOI: 10.1016/S1097-2765(02)00741-4.Milne T.A., Briggs S.D., Brock H.W., et al. MLL targets SET domain methyltransferase activity to Hox gene promoters. Mol Cell. 2002; 10(5): 1107–17. DOI: 10.1016/S1097-2765(02)00741-4.Wang X., Chen C.-W., Armstrong S.A. The role of DOT1L in the maintenance of leukemia gene expression. Curr Opin Genet Dev. 2016; 36: 68–72. DOI: 10.1016/j.gde.2016.03.015.Wang X., Chen C.-W., Armstrong S.A. The role of DOT1L in the maintenance of leukemia gene expression. Curr Opin Genet Dev. 2016; 36: 68–72. DOI: 10.1016/j.gde.2016.03.015.Kuntimaddi A., Achille N.J., Thorpe J., et al. Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential. Cell Rep. 2015; 11(5): 808–20. DOI: 10.1016/j.celrep.2015.04.004.Kuntimaddi A., Achille N.J., Thorpe J., et al. Degree of recruitment of DOT1L to MLL-AF9 defines level of H3K79 Di- and tri-methylation on target genes and transformation potential. Cell Rep. 2015; 11(5): 808–20. DOI: 10.1016/j.celrep.2015.04.004.Krivtsov A.V, Feng Z., Lemieux M.E., et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell. 2008; 14(5): 355–68. DOI: 10.1016/j.ccr.2008.10.001.Krivtsov A.V, Feng Z., Lemieux M.E., et al. H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell. 2008; 14(5): 355–68. DOI: 10.1016/j.ccr.2008.10.001.Nguyen A.T., Taranova O., He J., et al. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood. 2011; 117(25): 6912–22. DOI: 10.1182/blood-2011-02-334359.Nguyen A.T., Taranova O., He J., et al. DOT1L, the H3K79 methyltransferase, is required for MLL-AF9-mediated leukemogenesis. Blood. 2011; 117(25): 6912–22. DOI: 10.1182/blood-2011-02-334359.Sha L., Ayoub A., Cho U.-S., et al. Insights on the regulation of the MLL/ SET1 family histone methyltransferases. Biochim Biophys Acta Gene Regul Mech. 2020; 1863(7): 194561. DOI: 10.1016/j.bbagrm.2020.194561.Sha L., Ayoub A., Cho U.-S., et al. Insights on the regulation of the MLL/ SET1 family histone methyltransferases. Biochim Biophys Acta Gene Regul Mech. 2020; 1863(7): 194561. DOI: 10.1016/j.bbagrm.2020.194561.Hakimi M.-A., Dong Y., Lane W.S., et al. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2003; 278(9): 7234–9. DOI: 10.1074/jbc.M208992200.Hakimi M.-A., Dong Y., Lane W.S., et al. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2003; 278(9): 7234–9. DOI: 10.1074/jbc.M208992200.Harris W.J., Huang X., Lynch J.T., et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012; 21(4): 473–87. DOI: 10.1016/j.ccr.2012.03.014.Harris W.J., Huang X., Lynch J.T., et al. The histone demethylase KDM1A sustains the oncogenic potential of MLL-AF9 leukemia stem cells. Cancer Cell. 2012; 21(4): 473–87. DOI: 10.1016/j.ccr.2012.03.014.Blanc R.S., Richard S. Arginine methylation: The coming of age. Mol Cell. 2017; 65(1): 8–24. DOI: 10.1016/j.molcel.2016.11.003.Blanc R.S., Richard S. Arginine methylation: The coming of age. Mol Cell. 2017; 65(1): 8–24. DOI: 10.1016/j.molcel.2016.11.003.Swigut T., Wysocka J. H3K27 demethylases, at long last. Cell. 2007; 131(1): 29–32. DOI: 10.1016/j.cell.2007.09.026.Swigut T., Wysocka J. H3K27 demethylases, at long last. Cell. 2007; 131(1): 29–32. DOI: 10.1016/j.cell.2007.09.026.Zhao Q., Rank G., Tan Y.T., et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol. 2009; 16(3): 304–11. DOI: 10.1038/nsmb.1568.Zhao Q., Rank G., Tan Y.T., et al. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat Struct Mol Biol. 2009; 16(3): 304–11. DOI: 10.1038/nsmb.1568.Bedford M.T., Richard S. Arginine methylation: An emerging regulator of protein function. Mol Cell. 2005; 18(3): 263–72. DOI: 10.1016/j.molcel.2005.04.003.Bedford M.T., Richard S. Arginine methylation: An emerging regulator of protein function. Mol Cell. 2005; 18(3): 263–72. DOI: 10.1016/j.molcel.2005.04.003.Yang Y., Bedford M.T. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013; 13: 37–50. DOI: 10.1038/nrc3409.Yang Y., Bedford M.T. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013; 13: 37–50. DOI: 10.1038/nrc3409.Cui K., Zang C., Roh T.-Y., et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell. 2009; 4(1): 80–93. DOI: 10.1016/j.stem.2008.11.011.Cui K., Zang C., Roh T.-Y., et al. Chromatin signatures in multipotent human hematopoietic stem cells indicate the fate of bivalent genes during differentiation. Cell Stem Cell. 2009; 4(1): 80–93. DOI: 10.1016/j.stem.2008.11.011.Dimopoulos K., Grønbæk K. Epigenetic therapy in hematological cancers. APMIS. 2019; 127(5): 316–28. DOI: 10.1111/apm.12906.Dimopoulos K., Grønbæk K. Epigenetic therapy in hematological cancers. APMIS. 2019; 127(5): 316–28. DOI: 10.1111/apm.12906.Xie M., Jiang Q., Xie Y. Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: A meta-analysis with 1392 participants. Clin Lymphoma, Myeloma Leuk. 2015; 15(1): 22–8. DOI: 10.1016/j.clml.2014.04.010.Xie M., Jiang Q., Xie Y. Comparison between decitabine and azacitidine for the treatment of myelodysplastic syndrome: A meta-analysis with 1392 participants. Clin Lymphoma, Myeloma Leuk. 2015; 15(1): 22–8. DOI: 10.1016/j.clml.2014.04.010.He P.F., Zhou J.D., Yao D.M., et al. Efficacy and safety of decitabine in treatment of elderly patients with acute myeloid leukemia: A systematic review and metaanalysis. Oncotarget. 2017; 8(25): 41498–507. DOI: 10.18632/oncotarget.17241.He P.F., Zhou J.D., Yao D.M., et al. Efficacy and safety of decitabine in treatment of elderly patients with acute myeloid leukemia: A systematic review and metaanalysis. Oncotarget. 2017; 8(25): 41498–507. DOI: 10.18632/oncotarget.17241.Garcia-Manero G., Roboz G., Walsh K., et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: Phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019; 6(6): e317–27. DOI: 10.1016/S2352-3026(19)30029-8.Garcia-Manero G., Roboz G., Walsh K., et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: Phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019; 6(6): e317–27. DOI: 10.1016/S2352-3026(19)30029-8.Savona M.R., Odenike O., Amrein P.C., et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: A multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019; 6(4): e194–203. DOI: 10.1016/S2352-3026(19)30030-4.Savona M.R., Odenike O., Amrein P.C., et al. An oral fixed-dose combination of decitabine and cedazuridine in myelodysplastic syndromes: A multicentre, open-label, dose-escalation, phase 1 study. Lancet Haematol. 2019; 6(4): e194–203. DOI: 10.1016/S2352-3026(19)30030-4.Swords R.T., Coutre S., Maris M.B., et al. Pevonedistat, a first-in-class NEDD8- activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018; 131(13): 1415–24. DOI: 10.1182/blood-2017-09-805895.Swords R.T., Coutre S., Maris M.B., et al. Pevonedistat, a first-in-class NEDD8- activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018; 131(13): 1415–24. DOI: 10.1182/blood-2017-09-805895.Suraweera A., O’Byrne K.J., Richard D.J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front Oncol. 2018; 8: 92. DOI: 10.3389/fonc.2018.00092.Suraweera A., O’Byrne K.J., Richard D.J. Combination therapy with histone deacetylase inhibitors (HDACi) for the treatment of cancer: Achieving the full therapeutic potential of HDACi. Front Oncol. 2018; 8: 92. DOI: 10.3389/fonc.2018.00092San José-Enériz E., Gimenez-Camino N., Agirre X., et al. HDAC Inhibitors in acute myeloid leukemia. Cancers (Basel). 2019; 11(11): 1794. DOI: 10.3390/cancers11111794.San José-Enériz E., Gimenez-Camino N., Agirre X., et al. HDAC Inhibitors in acute myeloid leukemia. Cancers (Basel). 2019; 11(11): 1794. DOI: 10.3390/cancers11111794.Soriano A.O., Yang H., Faderl S., et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007; 110(7): 2302–8. DOI: 10.1182/blood-2007-03-078576.Soriano A.O., Yang H., Faderl S., et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood. 2007; 110(7): 2302–8. DOI: 10.1182/blood-2007-03-078576.Fredly H., Gjertsen B.T., Bruserud O. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: The effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenetics. 2013; 5(1): 12. DOI: 10.1186/1868-7083-5-12.Fredly H., Gjertsen B.T., Bruserud O. Histone deacetylase inhibition in the treatment of acute myeloid leukemia: The effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents. Clin Epigenetics. 2013; 5(1): 12. DOI: 10.1186/1868-7083-5-12.Marks P.A., Breslow R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007; 25(1): 84–90. DOI: 10.1038/nbt1272.Marks P.A., Breslow R. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug. Nat Biotechnol. 2007; 25(1): 84–90. DOI: 10.1038/nbt1272.Sayar H., Cripe L.D., Saliba A.N., et al. Combination of sorafenib, vorinostat and bortezomib for the treatment of poor-risk AML: Report of two consecutive clinical trials. Leuk Res. 2019; 77: 30–3. DOI: 10.1016/j.leukres.2018.12.011.Sayar H., Cripe L.D., Saliba A.N., et al. Combination of sorafenib, vorinostat and bortezomib for the treatment of poor-risk AML: Report of two consecutive clinical trials. Leuk Res. 2019; 77: 30–3. DOI: 10.1016/j.leukres.2018.12.011.Poole R.M. Belinostat: First global approval. Drugs. 2014; 74: 1543–54. DOI: 10.1007/s40265-014-0275-8.Poole R.M. Belinostat: First global approval. Drugs. 2014; 74: 1543–54. DOI: 10.1007/s40265-014-0275-8.Italiano A., Soria J.C., Toulmonde M., et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: A first-in-human, open-label, phase 1 study. Lancet Oncol. 2018; 19(5): 649–59. DOI: 10.1016/S1470-2045(18)30145-1.Italiano A., Soria J.C., Toulmonde M., et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: A first-in-human, open-label, phase 1 study. Lancet Oncol. 2018; 19(5): 649–59. DOI: 10.1016/S1470-2045(18)30145-1.Stein E.M., Garcia-Manero G., Rizzieri D.A., et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018; 131(24): 2662–9. DOI: 10.1182/blood-2017-12-818948.Stein E.M., Garcia-Manero G., Rizzieri D.A., et al. The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia. Blood. 2018; 131(24): 2662–9. DOI: 10.1182/blood-2017-12-818948.Pandey M.R., Wang E.S. What potential is there for LSD1 inhibitors to reach approval for AML? Expert Opin Emerg Drugs. 2019; 24(4): 205–12. DOI: 10.1080/14728214.2019.1694001.Pandey M.R., Wang E.S. What potential is there for LSD1 inhibitors to reach approval for AML? Expert Opin Emerg Drugs. 2019; 24(4): 205–12. DOI: 10.1080/14728214.2019.1694001.Garcia-Manero G., Montalban-Bravo G., Berdeja J.G., et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017; 123(6): 994–1002. DOI: 10.1002/cncr.30533.Garcia-Manero G., Montalban-Bravo G., Berdeja J.G., et al. Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes. Cancer. 2017; 123(6): 994–1002. DOI: 10.1002/cncr.30533.He P.-F., Zhou J.-D., Yao D.-M., et al. Efficacy and safety of decitabine in treatment of elderly patients with acute myeloid leukemia: A systematic review and metaanalysis. Oncotarget. 2017; 8(25): 41498–507. DOI: 10.18632/oncotarget.17241.He P.-F., Zhou J.-D., Yao D.-M., et al. Efficacy and safety of decitabine in treatment of elderly patients with acute myeloid leukemia: A systematic review and metaanalysis. Oncotarget. 2017; 8(25): 41498–507. DOI: 10.18632/oncotarget.17241.Curran M.P. Decitabine: A review of its use in older patients with acute myeloid leukaemia. Drugs Aging. 2013; 30(6): 447–58. DOI: 10.1007/s40266-013-0084-x.Curran M.P. Decitabine: A review of its use in older patients with acute myeloid leukaemia. Drugs Aging. 2013; 30(6): 447–58. DOI: 10.1007/s40266-013-0084-x.Odenike O. Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents. Hematology. 2017; 2017(1): 460–9. DOI: 10.1182/asheducation-2017.1.460.Odenike O. Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents. Hematology. 2017; 2017(1): 460–9. DOI: 10.1182/asheducation-2017.1.460.Roboz G.J., Kantarjian H.M., Yee K.W.L., et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018; 124(2): 325–34. DOI: 10.1002/cncr.31138.Roboz G.J., Kantarjian H.M., Yee K.W.L., et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer. 2018; 124(2): 325–34. DOI: 10.1002/cncr.31138.Guo S.-Q., Zhang Y.-Z. Histone deacetylase inhibition: An important mechanism in the treatment of lymphoma. Cancer Biol Med. 2012; 9(2): 85–9. DOI: 10.3969/j.issn.2095-3941.2012.02.001.Guo S.-Q., Zhang Y.-Z. Histone deacetylase inhibition: An important mechanism in the treatment of lymphoma. Cancer Biol Med. 2012; 9(2): 85–9. DOI: 10.3969/j.issn.2095-3941.2012.02.001.He L.Z., Tolentino T., Grayson P., et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 2001; 108(9): 1321–30. DOI: 10.1172/JCI11537.He L.Z., Tolentino T., Grayson P., et al. Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia. J Clin Invest. 2001; 108(9): 1321–30. DOI: 10.1172/JCI11537.Garcia-Manero G., Tambaro F.P., Bekele N.B., et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012; 30(18): 2204–10. DOI: 10.1200/JCO.2011.38.3265.Garcia-Manero G., Tambaro F.P., Bekele N.B., et al. Phase II trial of vorinostat with idarubicin and cytarabine for patients with newly diagnosed acute myelogenous leukemia or myelodysplastic syndrome. J Clin Oncol. 2012; 30(18): 2204–10. DOI: 10.1200/JCO.2011.38.3265.Garcia-Manero G., Othus M., Pagel J.M., et al. SWOG S1203: A randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without Vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Blood. 2016; 128(22): 901. DOI: 10.1182/blood.v128.22.901.901.Garcia-Manero G., Othus M., Pagel J.M., et al. SWOG S1203: A randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without Vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML). Blood. 2016; 128(22): 901. DOI: 10.1182/blood.v128.22.901.901.Walter R.B., Medeiros B.C., Gardner K.M., et al. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: A phase I/II study. Haematologica. 2014; 99(1): 54–9. DOI: 10.3324/haematol.2013.096545.Walter R.B., Medeiros B.C., Gardner K.M., et al. Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: A phase I/II study. Haematologica. 2014; 99(1): 54–9. DOI: 10.3324/haematol.2013.096545.Craddock C.F., Houlton A.E., Quek L.S., et al. Outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature. Clin Cancer Res. 2017; 23(21): 6430–40. DOI: 10.1158/1078-0432.CCR-17-1423.Craddock C.F., Houlton A.E., Quek L.S., et al. Outcome of azacitidine therapy in acute myeloid leukemia is not improved by concurrent vorinostat therapy but is predicted by a diagnostic molecular signature. Clin Cancer Res. 2017; 23(21): 6430–40. DOI: 10.1158/1078-0432.CCR-17-1423.How J., Minden M.D., Brian L., et al. A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia. Leuk Lymphoma. 2015; 56(10): 2793–802. DOI: 10.3109/10428194.2015.1018248.How J., Minden M.D., Brian L., et al. A phase I trial of two sequence-specific schedules of decitabine and vorinostat in patients with acute myeloid leukemia. Leuk Lymphoma. 2015; 56(10): 2793–802. DOI: 10.3109/10428194.2015.1018248.Van Veggel M., Westerman E., Hamberg P. Clinical pharmacokinetics and pharmacodynamics of panobinostat. Clin Pharmacokinet. 2018; 57(1): 21–9. DOI: 10.1007/s40262-017-0565-x.Van Veggel M., Westerman E., Hamberg P. Clinical pharmacokinetics and pharmacodynamics of panobinostat. Clin Pharmacokinet. 2018; 57(1): 21–9. DOI: 10.1007/s40262-017-0565-x.Schlenk R.F., Krauter J., Raffoux E., et al. Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia: Results from two clinical trials. Haematologica. 2018; 103(1): e25–8. DOI: 10.3324/haematol.2017.172411.Schlenk R.F., Krauter J., Raffoux E., et al. Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia: Results from two clinical trials. Haematologica. 2018; 103(1): e25–8. DOI: 10.3324/haematol.2017.172411.Tan P., Wei A., Mithraprabhu S., et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014; 4(1): e170. DOI: 10.1038/bcj.2013.68.Tan P., Wei A., Mithraprabhu S., et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014; 4(1): e170. DOI: 10.1038/bcj.2013.68.Bewersdorf J.P., Shallis R., Stahl M., et al. Epigenetic therapy combinations in acute myeloid leukemia: What are the options? Ther Adv Hematol. 2019; 10: 204062071881669. DOI: 10.1177/2040620718816698.Bewersdorf J.P., Shallis R., Stahl M., et al. Epigenetic therapy combinations in acute myeloid leukemia: What are the options? Ther Adv Hematol. 2019; 10: 204062071881669. DOI: 10.1177/2040620718816698.Pan D., Rampal R., Mascarenhas J. Clinical developments in epigenetic-directed therapies in acute myeloid leukemia. Blood Adv. 2020; 4(5): 970–82. DOI: 10.1182/bloodadvances.2019001245.Pan D., Rampal R., Mascarenhas J. Clinical developments in epigenetic-directed therapies in acute myeloid leukemia. Blood Adv. 2020; 4(5): 970–82. DOI: 10.1182/bloodadvances.2019001245.Eckschlager T., Plch J., Stiborova M., et al. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017; 18(7): 1414. DOI: 10.3390/ijms18071414.Eckschlager T., Plch J., Stiborova M., et al. Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci. 2017; 18(7): 1414. DOI: 10.3390/ijms18071414.Cheng Y.-C., Lin H., Huang M.-J., et al. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res. 2007; 31(10): 1403–11. DOI: 10.1016/j.leukres.2007.03.012.Cheng Y.-C., Lin H., Huang M.-J., et al. Downregulation of c-Myc is critical for valproic acid-induced growth arrest and myeloid differentiation of acute myeloid leukemia. Leuk Res. 2007; 31(10): 1403–11. DOI: 10.1016/j.leukres.2007.03.012.Kuendgen A., Schmid M., Schlenk R., et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006; 106(1): 112–119. DOI: 10.1002/cncr.21552.Kuendgen A., Schmid M., Schlenk R., et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006; 106(1): 112–119. DOI: 10.1002/cncr.21552.Попа А.В., Немировченко В.С., Флейшман Е.В. и др. Ингибиторы гистондеацетилазы и ДНК-метилтрансферазы в лечении детей, больных острым миелоидным лейкозом, их эффективность и место в терапии. Российский журнал детской гематологии и онкологии. 2016; 3(4): 48–54.Popa A.V., Nemirovchenko V.S., Fleyshman E.V., et al. Inhibitors of histon deacetylase (HDAC) and DNA methyltransferase in treatment children with acute myeloid leukemia, effectiveness and place. Russian Journal of Pediatric Hematology and Oncology. 2016; 3(4): 48–54. DOI: 10.17650/2311-1267-2016-3-4-48-54 (In Russian).Brown P.J., Müller S. Open access chemical probes for epigenetic targets. Future Med Chem. 2015; 7(14): 1901–17. DOI: 10.4155/fmc.15.127.Brown P.J., Müller S. Open access chemical probes for epigenetic targets. Future Med Chem. 2015; 7(14): 1901–17. DOI: 10.4155/fmc.15.127.McCabe M.T., Mohammad H.P., Barbash O., et al. Targeting histone methylation in cancer. Cancer J (United States). 2017; 23(5): 292–301. DOI: 10.1097/PPO.0000000000000283.McCabe M.T., Mohammad H.P., Barbash O., et al. Targeting histone methylation in cancer. Cancer J (United States). 2017; 23(5): 292–301. DOI: 10.1097/PPO.0000000000000283.Li B., Chng W.J. EZH2 abnormalities in lymphoid malignancies: Underlying mechanisms and therapeutic implications. J Hematol Oncol. 2019; 12: 118. DOI: 10.1186/s13045-019-0814-6.Li B., Chng W.J. EZH2 abnormalities in lymphoid malignancies: Underlying mechanisms and therapeutic implications. J Hematol Oncol. 2019; 12: 118. DOI: 10.1186/s13045-019-0814-6.Vaswani R.G., Gehling V.S., Dakin L.A., et al. Identifi cation of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifl uoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med Chem. 2016; 59(21): 9928–41. DOI: 10.1021/acs.jmedchem.6b01315.Vaswani R.G., Gehling V.S., Dakin L.A., et al. Identifi cation of (R)-N-((4-Methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifl uoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide (CPI-1205), a potent and selective inhibitor of histone methyltransferase EZH2, suitable for phase I clinical trials for B-cell lymphomas. J Med Chem. 2016; 59(21): 9928–41. DOI: 10.1021/acs.jmedchem.6b01315.Daigle S.R., Olhava E.J., Therkelsen C.A., et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013; 122(6): 1017–25. DOI: 10.1182/blood-2013-04-497644.Daigle S.R., Olhava E.J., Therkelsen C.A., et al. Potent inhibition of DOT1L as treatment of MLL-fusion leukemia. Blood. 2013; 122(6): 1017–25. DOI: 10.1182/blood-2013-04-497644.Alinari L., Mahasenan K.V., Yan F., et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood. 2015; 125(16): 2530–43. DOI: 10.1182/blood-2014-12-619783.Alinari L., Mahasenan K.V., Yan F., et al. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood. 2015; 125(16): 2530–43. DOI: 10.1182/blood-2014-12-619783.Jin Y., Zhou J., Xu F., et al. Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. J Clin Invest. 2016; 126(10): 3961–80. DOI: 10.1172/JCI85239.Jin Y., Zhou J., Xu F., et al. Targeting methyltransferase PRMT5 eliminates leukemia stem cells in chronic myelogenous leukemia. J Clin Invest. 2016; 126(10): 3961–80. DOI: 10.1172/JCI85239.Chan-Penebre E., Kuplast K.G., Majer C.R., et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015; 11(6): 432–7. DOI: 10.1038/nchembio.1810.Chan-Penebre E., Kuplast K.G., Majer C.R., et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015; 11(6): 432–7. DOI: 10.1038/nchembio.1810.Adamo A., Sesé B., Boue S., et al. LSD1 regulates the balance between selfrenewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011; 13(6): 652–9. DOI: 10.1038/ncb2246.Adamo A., Sesé B., Boue S., et al. LSD1 regulates the balance between selfrenewal and differentiation in human embryonic stem cells. Nat Cell Biol. 2011; 13(6): 652–9. DOI: 10.1038/ncb2246.Whyte W.A., Bilodeau S., Orlando D.A., et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature. 2012; 482(7384): 221–5. DOI: 10.1038/nature10805.Whyte W.A., Bilodeau S., Orlando D.A., et al. Enhancer decommissioning by LSD1 during embryonic stem cell differentiation. Nature. 2012; 482(7384): 221–5. DOI: 10.1038/nature10805.

The authors declare that there are no conflicts of interest present.