open access

Vol 6, No 6 (2010)
Review paper
Published online: 2011-02-24
Get Citation

Epigenetics in hematooncology

Krzysztof Giannopoulos
Onkol. Prak. Klin 2010;6(6):333-342.

open access

Vol 6, No 6 (2010)
REVIEW ARTICLES
Published online: 2011-02-24

Abstract

Epigenetical changes are reversible modifications of genomic DNA that result in changes in gene expression profile. In tumorigenesis common DNA hypomethylation leads to activation of genes connected with proliferation, that escape from the control of suppressor genes which are silenced due to CpG islands hypermethylation. The crucial role of epigenetic deregulation in tumor progression and reversible character of these modifications leads to the great interest of epigenetic therapies in hematooncology. The best characterized epigenetic changes are DNA hypermethylation and histone deacetylation, therefore first epigenetic drugs are hypomethylating agents and histone deacetylase inhibitors. Three epigenetic drugs are nowadays registered by FDA and EMEA for the therapy: azacitidine, decitabine and vorinostat. Vorinostat is effective in cutaneous T-cell lymphomas therapy while the greatest expectations are linked to drugs that might be effective in treatment of the most common hematological malignancies. In current review epigenetical regulation as well as results of the first clinical trials in acute myeloid leukemia, myelodysplastic syndrome and chronic lymphocytic leukemia were described.

Onkol. Prak. Klin. 2010; 6, 6: 333–342

Abstract

Epigenetical changes are reversible modifications of genomic DNA that result in changes in gene expression profile. In tumorigenesis common DNA hypomethylation leads to activation of genes connected with proliferation, that escape from the control of suppressor genes which are silenced due to CpG islands hypermethylation. The crucial role of epigenetic deregulation in tumor progression and reversible character of these modifications leads to the great interest of epigenetic therapies in hematooncology. The best characterized epigenetic changes are DNA hypermethylation and histone deacetylation, therefore first epigenetic drugs are hypomethylating agents and histone deacetylase inhibitors. Three epigenetic drugs are nowadays registered by FDA and EMEA for the therapy: azacitidine, decitabine and vorinostat. Vorinostat is effective in cutaneous T-cell lymphomas therapy while the greatest expectations are linked to drugs that might be effective in treatment of the most common hematological malignancies. In current review epigenetical regulation as well as results of the first clinical trials in acute myeloid leukemia, myelodysplastic syndrome and chronic lymphocytic leukemia were described.

Onkol. Prak. Klin. 2010; 6, 6: 333–342

Get Citation

Keywords

epigenetics; hematooncology

About this article
Title

Epigenetics in hematooncology

Journal

Oncology in Clinical Practice

Issue

Vol 6, No 6 (2010)

Article type

Review paper

Pages

333-342

Published online

2011-02-24

Bibliographic record

Onkol. Prak. Klin 2010;6(6):333-342.

Keywords

epigenetics
hematooncology

Authors

Krzysztof Giannopoulos

References (68)
  1. Constantinides PG, Jones PA, Gevers W. Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature. 1977; 267(5609): 364–366.
  2. Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980; 20(1): 85–93.
  3. Sealy L, Chalkley R. The effect of sodium butyrate on histone modification. Cell. 1978; 14(1): 115–121.
  4. Lozzio CB, Lozzio BB, Machado EA, et al. Effects of sodium butyrate on human chronic myelogenous leukaemia cell line K562. Nature. 1979; 281(5733): 709–710.
  5. Karon M, Sieger L, Leimbrock S, et al. 5-Azacytidine: a new active agent for the treatment of acute leukemia. Blood. 1973; 42(3): 359–365.
  6. Esteller M. Epigenetics in cancer. N Engl J Med. 2008; 358(11): 1148–1159.
  7. Bueno MJ, Pérez de Castro I, Gómez de Cedrón M, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008; 13(6): 496–506.
  8. Mann BS, Johnson JR, Cohen MH, et al. FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist. 2007; 12(10): 1247–1252.
  9. Musolino C, Sant'antonio E, Penna G, et al. Epigenetic therapy in myelodysplastic syndromes. Eur J Haematol. 2010; 84(6): 463–473.
  10. Boultwood J, Wainscoat JS. Gene silencing by DNA methylation in haematological malignancies. Br J Haematol. 2007; 138(1): 3–11.
  11. Quesnel B, Guillerm G, Vereecque R, et al. Methylation of the p15(INK4b) gene in myelodysplastic syndromes is frequent and acquired during disease progression. Blood. 1998; 91(8): 2985–2990.
  12. Kim M, Oh B, Kim SY, et al. p15INK4b methylation correlates with thrombocytopenia, blast percentage, and survival in myelodysplastic syndromes in a dose dependent manner: quantitation using pyrosequencing study. Leuk Res. 2010; 34(6): 718–722.
  13. Cohen O, Kimchi A. DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. Cell Death Differ. 2001; 8(1): 6–15.
  14. Iwai M, Kiyoi H, Ozeki K, et al. Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2005; 19(8): 1367–1375.
  15. Silverman LR, Holland JF, Weinberg RS, et al. Effects of treatment with 5-azacytidine on the in vivo and in vitro hematopoiesis in patients with myelodysplastic syndromes. Leukemia. 1993; 7 Suppl 1: 21–29.
  16. Silverman LR, Holland JF, Demakos EP. Azacytidine (Aza C) in myelodysplastic syndrome (MDS), CALGB studies 8421 abd 8921. Ann Hematol. 1994; 68: A12.
  17. Kornblith AB, Herndon JE, Silverman LR, 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. 2002; 20(10): 2429–2440.
  18. Silverman LR, McKenzie DR, Peterson BL, et al. Cancer and Leukemia Group B. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol. 2006; 24(24): 3895–3903.
  19. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. 1999; 17(12): 3835–3849.
  20. Cheson BD, Bennett JM, Kantarjian H, et al. World Health Organization(WHO) international working group. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000; 96(12): 3671–3674.
  21. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. International Vidaza High-Risk MDS Survival Study Group. 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. 2009; 10(3): 223–232.
  22. Gurion R, Vidal L, Gafter-Gvili A, et al. 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome--a systematic review and meta-analysis. Haematologica. 2010; 95(2): 303–310.
  23. Wijermans PW, Lübbert M, Verhoef G, et al. An epigenetic approach to the treatment of advanced MDS; the experience with the DNA demethylating agent 5-aza-2'-deoxycytidine (decitabine) in 177 patients. Ann Hematol. 2005; 84 Suppl 1: 9–17.
  24. Kantarjian H, Issa JPJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006; 106(8): 1794–1803.
  25. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood. 2007; 109(1): 52–57.
  26. Kantarjian HM, O'Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer. 2007; 109(2): 265–273.
  27. Steensma DP, Baer MR, Slack JL, et al. Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. J Clin Oncol. 2009; 27(23): 3842–3848.
  28. Galm O, Wilop S, Lüders C, et al. Clinical implications of aberrant DNA methylation patterns in acute myelogenous leukemia. Ann Hematol. 2005; 84 Suppl 1: 39–46.
  29. Figueroa ME, Lugthart S, Li Y, et al. DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell. 2010; 17(1): 13–27.
  30. Herman JG, Civin CI, Issa JP, et al. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res. 1997; 57(5): 837–841.
  31. Wong IH, Ng MH, Huang DP, et al. Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood. 2000; 95(6): 1942–1949.
  32. Li Q, Kopecky KJ, Mohan A, et al. Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia. Clin Cancer Res. 1999; 5(5): 1077–1084.
  33. Bug G, Ritter M, Wassmann B, et al. Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia. Cancer. 2005; 104(12): 2717–2725.
  34. Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005; 84 Suppl 1: 61–66.
  35. Corcoran M, Parker A, Orchard J, et al. ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia. Haematologica. 2005; 90(8): 1078–1088.
  36. Raval A, Lucas DM, Matkovic JJ, et al. TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia. J Clin Oncol. 2005; 23(17): 3877–3885.
  37. Strathdee G, Sim A, Parker A, et al. Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL. Leukemia. 2006; 20(7): 1326–1329.
  38. Raval A, Tanner SM, Byrd JC, et al. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell. 2007; 129(5): 879–890.
  39. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002; 21(35): 5427–5440.
  40. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000; 343(26): 1910–1916.
  41. Mertens D, Wolf S, Schroeter P, et al. Down-regulation of candidate tumor suppressor genes within chromosome band 13q14.3 is independent of the DNA methylation pattern in B-cell chronic lymphocytic leukemia. Blood. 2002; 99(11): 4116–4121.
  42. Rush LJ, Raval A, Funchain P, et al. Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets. Cancer Res. 2004; 64(7): 2424–2433.
  43. Kanduri M, Cahill N, Göransson H, et al. Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia. Blood. 2010; 115(2): 296–305.
  44. Blum KA, Liu Z, Lucas DM, et al. Phase I trial of low dose decitabine targeting DNA hypermethylation in patients with chronic lymphocytic leukaemia and non-Hodgkin lymphoma: dose-limiting myelosuppression without evidence of DNA hypomethylation. Br J Haematol. 2010; 150(2): 189–195.
  45. Schrump DS. Cytotoxicity mediated by histone deacetylase inhibitors in cancer cells: mechanisms and potential clinical implications. Clin Cancer Res. 2009; 15(12): 3947–3957.
  46. Richon VM, Sandhoff TW, Rifkind RA, et al. Histone deacetylase inhibitor selectively induces p21WAF1 expression and gene-associated histone acetylation. Proc Natl Acad Sci U S A. 2000; 97(18): 10014–10019.
  47. Sandor V, Senderowicz A, Mertins S, et al. P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer. 2000; 83(6): 817–825.
  48. Zhao Y, Lu S, Wu L, et al. Acetylation of p53 at lysine 373/382 by the histone deacetylase inhibitor depsipeptide induces expression of p21(Waf1/Cip1). Mol Cell Biol. 2006; 26(7): 2782–2790.
  49. Dai Y, Rahmani M, Dent P, et al. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol. 2005; 25(13): 5429–5444.
  50. Wang Y, Wang SY, Zhang XH, et al. FK228 inhibits Hsp90 chaperone function in K562 cells via hyperacetylation of Hsp70. Biochem Biophys Res Commun. 2007; 356(4): 998–1003.
  51. Nishioka C, Ikezoe T, Yang J, et al. MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells. Leuk Res. 2008; 32(9): 1382–1392.
  52. Robbins AR, Jablonski SA, Yen TJ, et al. Inhibitors of histone deacetylases alter kinetochore assembly by disrupting pericentromeric heterochromatin. Cell Cycle. 2005; 4(5): 717–726.
  53. Kim SH, Jeong JW, Park JAe, et al. Regulation of the HIF-1alpha stability by histone deacetylases. Oncol Rep. 2007; 17(3): 647–651.
  54. Suzuki T, Yokozaki H, Kuniyasu H, et al. Effect of trichostatin A on cell growth and expression of cell cycle- and apoptosis-related molecules in human gastric and oral carcinoma cell lines. Int J Cancer. 2000; 88(6): 992–997.
  55. Rosato RR, Almenara JA, Grant S. The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. Cancer Res. 2003; 63(13): 3637–3645.
  56. Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood. 2006; 108(10): 3441–3449.
  57. Inoue H, Shiraki K, Ohmori S, et al. Histone deacetylase inhibitors sensitize human colonic adenocarcinoma cell lines to TNF-related apoptosis inducing ligand-mediated apoptosis. Int J Mol Med. 2002; 9(5): 521–525.
  58. Weiser TS, Ohnmacht GA, Guo ZS, et al. Induction of MAGE-3 expression in lung and esophageal cancer cells. Ann Thorac Surg. 2001; 71(1): 295–301.
  59. Weiser TS, Guo ZS, Ohnmacht GA, et al. Sequential 5-Aza-2 deoxycytidine-depsipeptide FR901228 treatment induces apoptosis preferentially in cancer cells and facilitates their recognition by cytolytic T lymphocytes specific for NY-ESO-1. J Immunother. 2001; 24(2): 151–161.
  60. Munshi A, Kurland JF, Nishikawa T, et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res. 2005; 11(13): 4912–4922.
  61. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol. 2007; 25(21): 3109–3115.
  62. Richardson P, Mitsiades C, Colson K, et al. Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma. 2008; 49(3): 502–507.
  63. Crump M, Coiffier B, Jacobsen ED, et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large-B-cell lymphoma. Ann Oncol. 2008; 19(5): 964–969.
  64. Garcia-Manero G, Yang H, Bueso-Ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008; 111(3): 1060–1066.
  65. Dummer R, Hymes K, Sterry W, et al. Vorinostat in combination with bexarotene in advanced cutaneous T-cell lymphoma: A phase I study. J Clin Oncol. 2009; 27(supl.): abstr.
  66. Badros A, Burger AM, Philip S, et al. Phase I study of vorinostat in combination with bortezomib for relapsed and refractory multiple myeloma. Clin Cancer Res. 2009; 15(16): 5250–5257.
  67. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia. 2006; 20(2): 212–217.
  68. 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.

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

Wydawcą serwisu jest  "Via Medica sp. z o.o." sp.k., ul. Świętokrzyska 73, 80–180 Gdańsk

tel.:+48 58 320 94 94, faks:+48 58 320 94 60, e-mail:  viamedica@viamedica.pl