Epigenetics in Oncohematology: Brief Review

Objective. To discuss historical aspects of epigenetics as an independent branch of biology, as well as to describe post-translational modifications of DNA and histones (PTMs) as epigenetic events.

Methods. Review of fundamentals of epigenetics in topical articles and abstracts: DNA methylation, histones acetylation, phosphorylation, methylation, ubiquitination, and SUMOylation in the development of oncological disorders. The effect of so-called interfering RNA on epigenetic processes has drawn much attention in recent years. The RNA interference (RNAi) can be used to detect epigenetic regulators for the purpose of potential pharmacologic effect on tumor cells. The significance of small I-BET and JQ1 molecules in the antitumor response is considered. The role of BET proteins in hematologic malignancies is discussed separately.

Conclusions. At present, DNA methyltransferase inhibitors (hypomethylating agents) and histone deacetylase inhibitors (which represent a brand new approach, an epigenetic therapy) are used for the treatment of hematopoietic neoplasms.

• Anton Dmitrievich Shirin N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478 ; ФГБНУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478
• G.I. Kaletin N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478 ; ФГБНУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478
• O.Yu. Baranova N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478 ; ФГБНУ «Российский онкологический научный центр им. Н.Н. Блохина», Каширское ш., д. 24, Москва, Российская Федерация, 115478

1. Уоддингтон К.Х. Основные биологические концепции. В кн.: На пути к теоретической биологии. Часть I. Пролегомены. М.: Мир, 1970:11–38. [Waddington CH. Basic ideas of biology. In: Waddington CH, ed. Na puti k teoreticheskoi biologii. Chast’ I. Prolegomeny. (Towards a theoretical biology. Part I. Prolegomena.) Moscow: Mir Publ.; 1970. pp. 11–38. (In Russ)]
2. Shannon K, Armstrong SA. Genetics, epigenetics, and leukemia. N Engl J Med. 2010;363(25):2460–1. doi: 10.1056/NEJMe1012071. DOI: https://doi.org/10.1056/NEJMe1012071
3. Ayton PM, Cleary ML. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene Rev. 2001;20(40):5695–707. doi: 10.1038/sj.onc.1204639. DOI: https://doi.org/10.1038/sj.onc.1204639
4. Daser A, Rabbitts TH. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev. 2004;18(9):965–74. doi: 10.1101/gad.1195504. DOI: https://doi.org/10.1101/gad.1195504
5. Manodoro F, Marzec J, Chaplin T, et al. Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia. Blood. 2014;123(13):2066–74. doi: 10.1182/blood-2012-12-469833. DOI: https://doi.org/10.1182/blood-2012-12-469833
6. Huntly BJP, Johnson PWM. Targeting Epigenetic Readers in Hematologic Malignancies: A Good BET? The Hematologist. 2012;10(2). http://www.hematology.org/Thehematologist/Mini-Review/1181.aspx. DOI: https://doi.org/10.1182/hem.V9.2.1181
7. Wu SY, Chiang CM. The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation. J Biol Chem. 2007;282(18):13141–5. doi: 10.1074/jbc.r700001200. DOI: https://doi.org/10.1074/jbc.R700001200
8. Fowler T, Sen R, Roy AL. Regulation of primary response genes. Mol Cell. 2011;44(3):348–60. doi: 10.1016/j.molcel.2011.09.014. DOI: https://doi.org/10.1016/j.molcel.2011.09.014
9. Filippakopoulos P, Qi J, Picaud S, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–73. doi: 10.1038/nature09504. DOI: https://doi.org/10.1038/nature09504
10. Nicodeme E, Jeffrey KL, Schaefer U, et al. Suppression of inflammation by a synthetic histone mimic. Nature. 2010;468(7327):1119–23. doi: 10.1038/nature09589. DOI: https://doi.org/10.1038/nature09589
11. Dawson MA, Prinjha RK, Dittmann A, et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature. 2011;478(7370):529–33. doi: 10.1038/nature10509. DOI: https://doi.org/10.1038/nature10509
12. Smith E, Lin C, Shilatifard A. The super elongation complex (SEC) and MLL in development and disease. Genes Dev. 2011;25(7):661–72. doi: 10.1101/gad.2015411. DOI: https://doi.org/10.1101/gad.2015411
13. Zuber J, Shi J, Wang E, et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011;478(7370):524–8. doi: 10.1038/nature10334. DOI: https://doi.org/10.1038/nature10334
14. Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17. doi: 10.1016/j.cell.2011.08.017. DOI: https://doi.org/10.1016/j.cell.2011.08.017
15. Mertz JA, Conery AR, Bryant BM, et al. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci USA. 2011;108(40):16669–74. doi: 10.1073/pnas.1108190108. DOI: https://doi.org/10.1073/pnas.1108190108
16. Thompson CB. Targeting Metabolic Inputs into Epigenetic Regulations of Acute Leukemia. Blood. 2013;122: Abstract SCI-26. DOI: https://doi.org/10.1182/blood.V122.21.SCI-26.SCI-26
17. http://medbiol.ru/medbiol/epigenetica/0005e8fd.htm.
18. http://moikompas.ru/compas/modification_histones.
19. Mai A, Altucci L. Epi-drugs to fight cancer: from chemistry to cancer treatment, the road ahead. Int J Biochem Cell Biol. 2009;41(1):199–213. doi: 10.1016/j.biocel.2008.08.020. DOI: https://doi.org/10.1016/j.biocel.2008.08.020
20. Чехун В. Эпигенетика рака. Колонка главного редактора. Онкология. 2008;10(3):301–2. [Chekhun V. Epigenetics of cancer. Editorial column. Onkologiya. 2008;10(3):301–2. (In Russ)]
21. http://moikompas.ru/compas/avaiserman.