Abstract
DNA methylation provides a major epigenetic code (besides histone modification) of the lineage- and developmentspecific genes (such as regulators of differentiation in the hematopoietic lineages) that control expression of normal cells. However, DNA methylation is also involved in malignancies because aberrant methylating gene activity occurs during leukemic transformation.Thus, genes such as tumor suppressor genes, growth-regulatory genes, and adhesion molecules are often silenced in various hematopoietic malignancies by epigenetic inactivation via DNA hypermethylation. This inactivation is frequently seen not only in transformed cell lines but also in primary leukemia cells. Because this defect is amenable to reversion by pharmacologic means, agents that inhibit DNA methylation have been developed to specifically target this hypermethylation defect in leukemia and preleukemia cases. The most clinically advanced agents, the azanucleosides 5-azacytidine and 5-aza-2′-deoxycytidine (decitabine), were discovered more than 25 years ago, when their methylation-inhibitory activities, even at low concentrations, became apparent.Although both of these agents, like cytarabine, had been clinically used until then at high doses, the redevelopment of these agents for low-dose schedules has revealed very interesting clinical activities for treating myelodysplasia (MDS) and acute myeloid leukemia (AML). Because these diseases occur mostly in patients over 60 years of age, low-dose schedules with these compounds provide a very promising approach in such patient groups by virtue of their low nonhematologic toxicity profiles. In the present review, we describe the development of treatments that target DNA hypermethylation in MDS and AML, and clinical results are presented. In addition, pharmacologic DNA demethylation may be viewed as a platform for biological modification of malignant cells to become sensitized (or resensitized) to secondary signals, such as differentiating signals (retinoids, vitamin D3) and hormonal signals (eg, estrogen receptor in breast cancer cells, androgen receptor in prostate cancer cells). Finally, an in vitro synergism between the reactivating potency of demethylating agents and inhibitors of histone deacetylation has been tested in several pilot studies of AML and MDS treatment. Finally, gene reactivation by either group of compounds results in therapeutically meaningful reactivation of fetal hemoglobin in patients with severe hemoglobinopathies, extending the therapeutic range of derepressive epigenetic agents to nonmalignant hematopoietic disorders.
Similar content being viewed by others
References
Bird AP. CpG-rich islands and the function of DNA methylation. Nature. 1986;321:209–213.
Cross SH, Bird AP. CpG islands and genes. Curr Opin Genet Dev. 1995;5:309–314.
Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J Mol Biol. 1987;196:261–282.
Graff JR, Herman JG, Myohanen S, Baylin SB,Vertino PM. Mapping patterns of CpG island methylation in normal and neoplastic cells implicates both upstream and downstream regions in de novo methylation. J Biol Chem. 1997;272:22322–22329.
Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196.
Barlow DP. Gametic imprinting in mammals. Science. 1995;270:1610–1613.
Goto T, Monk M. Regulation of X-chromosome inactivation in development in mice and humans. Microbiol Mol Biol Rev. 1998;62:362–378.
Bird AP, Wolffe AP. Methylation-induced repression: belts, braces, and chromatin. Cell. 1999;99:451–454.
Jones PL, Veenstra GJ, Wade PA, et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 1998;19:187–189.
Jones PL, Wolffe AP. Relationships between chromatin organization and DNA methylation in determining gene expression. Semin Cancer Biol. 1999;9:339–347.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet. 2003;33(suppl):245–254.
Kouzarides T. Histone methylation in transcriptional control. Curr Opin Genet Dev. 2002;12:198–209.
Pfeifer GP, Steigerwald S, Boehm TLJ, Drahovsky D. DNA methylation levels in acute human leukemia. Cancer Lett. 1988;39:185–192.
Wahlfors J, Hiltunen H, Heinonen E, Hämäläinen E, Alhoionen L, Jänne J. Genomic hypomethylation in human chronic lymphocytic leukemia. Blood. 1992;80:2074–2080.
Lyko F, Stach D, Brenner A, et al. Quantitative analysis of DNA methylation in chronic lymphocytic leukemia patients. Electrophoresis. 2004;25:1–6.
Lübbert M, Brugger W, Mertelsmann R, Kanz L. Developmental regulation of myeloid gene expression and demethylation during ex vivo culture of peripheral blood progenitor cells. Blood. 1996;87:447–455.
Sakashita K, Koike K, Kinoshita T, et al. Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. J Clin Invest. 2001;108:1195–1204.
Chim CS, Liang R, Kwong YL. Hypermethylation of gene promoters in hematological neoplasia. Hematol Oncol. 2002;20:167–176.
Lehmann U, Brakensiek K, Kreipe H. Role of epigenetic changes in hematological malignancies. Ann Hematol. 2004;83:137–152.
Drexler HG. Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia. 1998;12:845–859.
Lübbert M. Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes? Leukemia. 2003;17:1762–1764.
Di Croce L, Raker VA, Corsaro M, et al. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002;295:1079–1082.
Momparler RL, Cote S, Eliopoulos N. Pharmacological approach for optimization of the dose schedule of 5-aza-2′-deoxycytidine (decitabine) for the therapy of leukemia. Leukemia. 1997;11(suppl 1):1–6.
Lübbert M. DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. Curr Top Microbiol Immunol. 2000;249:135–164.
Miller KB, Kim K, Morrison FS, et al. The evaluation of low-dose cytarabine in the treatment of myelodysplastic syndromes: a phase- III intergroup study. Ann Hematol. 1992;65:162–168.
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.
Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syn drome:A study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20:2429–2440.
Kornblith AB, Herndon JE 2nd, Silverman LR, et al. Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study. J Clin Oncol. 2002;20:2441–2452.
Wijermans PW, Krulder JW, Huijgens PC, Neve P. Continuous infusion of low-dose 5-aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome. Leukemia. 1997;11(suppl 1):19–23.
Wijermans PW, Lübbert M, Verhoef G. Low dose decitabine for elderly high risk MDS patients: who will respond? [abstract]. Blood. 2002;100:96a.
Lübbert M, Wijermans PW, Kunzmann R, et al. Cytogenetic responses in high-risk myelodysplastic syndrome following lowdose treatment with the DNA methylation inhibitor 5-aza-2′- deoxycytidine. Br J Haematol. 2001;114:349–357.
Hiddemann W, Kern W, Schoch C, et al. Management of acute myeloid leukemia in elderly patients. J Clin Oncol. 1999;17:3569–3576.
Pinto A, Zagonel V, Attadia V, et al. 5-Aza-2′-deoxycytidine as a differentiation inducer in acute myeloid leukaemias and myelodysplastic syndromes of the elderly. Bone Marrow Transplant. 1989;4(suppl 3):28–32.
Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of lowdose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640.
Trus MR, Bordeleau LJ, San-Marina S, Minden MD. 5-Aza-2′- deoxycytidine (5-Aza-2-Cdr) reverses CpG methylation of the retinoic acid receptor ′ (RAR ′) promoter and restores retinoid responsiveness in non M3 acute myelogenous leukemia (AML) blasts [abstract]. Blood. 2001;98. Abstract 1925.
van der Ploeg LH, Flavell RA. DNA methylation in the human gamma delta beta-globin locus in erythroid and nonerythroid tissues. Cell. 1980;19:947–958.
DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci U S A. 1982;79:4428–4431.
Lowrey CH, Nienhuis AW. Brief report: treatment with azacitidine of patients with end-stage β-thalassemia. N Engl J Med. 1993;329:845–848.
Koshy H, Molokie R, Dom L, et al. Augmentation of fetal hemoglobin (HbF) levels by low dose short duration 5-aza-2′-deoxycytidine (decitabine) administration in sickle cell anemia patients who had no HbF elevation following hydroxyurea therapy [abstract]. Blood. 1998;92(suppl 1):306b.
Saunthararajah Y, Hillery CA, Lavelle D, et al. Effects of 5-aza-2′- deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood. 2003;102:3865–3870.
Lavelle D, DeSimone J, Hankewych M, Kousnetzova T, Chen YH. Decitabine induces cell cycle arrest at the G1 phase via p21 (WAF1) and the G2/M phase via the p38 MAP kinase pathway. Leuk Res. 2003;27:999–1007.
Chan AT, Tao Q, Robertson KD, et al. Azacitidine induces demethylation of the Epstein-Barr virus genome in tumors. J Clin Oncol. 2004;22:1373–1381.
Gore SD,Weng LJ, Figg WD, et al. Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res. 2002;8:963–970.
Cameron EE, Bachman KE, Myohanen S, Herman JG, Baylin SB. Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer. Nat Genet. 1999;21:103–107.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Rüter, B., Wijermans, P.W. & Lübbert, M. DNA Methylation as a Therapeutic Target in Hematologic Disorders: Recent Results in Older Patients with Myelodysplasia and Acute Myeloid Leukemia. Int J Hematol 80, 128–135 (2004). https://doi.org/10.1532/IJH97.04094
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1532/IJH97.04094