65
Views
13
CrossRef citations to date
0
Altmetric
Review

The silence of the genes: epigenetic disturbances in haematopoietic malignancies

, &
Pages 45-61 | Published online: 22 Apr 2005

Bibliography

  • BIRD AP: CpG-rich islands and the function of DNA methylation. Nature (1986) 321(6067):209–213.
  • •Excellent review defining the role of CpG islands and their implications for gene expression.
  • GARDINER-GARDEN M, FROMMER M: CpG islands invertebrate genomes. Mol. Biol. (1987) 196(2):261–282.
  • •Formal criteria for CpG island definition are described that are still very valid.
  • CROSS SH, BIRD AP: CpG islands and genes. Curr. Opin. Genet. Dev. (1995) 5(3):309–314.
  • 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. I Biol. Chem. (1997) 272(35):22322–22329.
  • LOBBERT M, MILLER CW, KOEFFLER HP: Changes of DNA methylation and chromatin structure in the human myeloperoxidase gene during myeloid differentiation. Blood (1991) 78(2):345–56.
  • 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.
  • BIRD AP, WOLFFE AP: Methylation-induced repression-belts, braces, and chromatin. Cell (1999) 99(5):451–454.
  • •Comprehensive review outlining the interaction between DNA methylation and histone modification in gene silencing.
  • JONES PL, VEENSTRA GJ, WADE PA et al: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat. Genet. (1998) 19(2):187–191.
  • ••Seminal discovery of recruitment ofHDAC activity to methylated DNA via the MeCP2 DNA-binding protein.
  • JONES PL, WOLFFE AP: Relationships between chromatin organization and DNA methylation in determining gene expression. Semin. Cancer Biol. (1999) 9(5):339–347.
  • NAN X, BIRD A: The biological functions of the methyl-CpG-binding protein MeCP2 and its implication in Rett syndrome. Broth Dev. (2001) 23\(Suppl. 1):32–37.
  • LUBBERT 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(2)447–455.
  • LUBBERT M, HENSCHLER R, KREUTZ M, ANDREESEN R, MERTELSMANN R, HERRMANN F: The human lysozyme gene undergoes stepwise demethylation during phagocyte maturation. Leukemia (1997) 11(7):990–997.
  • LUBBERT M, TOBLER A, DASKALAKIS M: Cytosine demethylation of the proteinase-3/myeloblastin primary granule protease gene during phagocyte development. Leukemia (1999) 13(9):1420–1427.
  • FELGNER J, KREIPE H, HEIDORN K et al.: Lineage-specific methylation of the c-fms gene in blood cells and macrophages. Leukemia (1992) 6(5):420–425.
  • FELGNER J, HEIDORN K, KORBACHER D, FRAHM SO, PARWARESCH R: Cell lineage specificity in G-CSF receptor gene methylation. Leukemia (1999) 13(4):530–534.
  • DODGE JE, MUNSON C, LIST AF: KG-1 and KG-la model the p15 CpG island methylation observed in acute myeloid leukemia patients. Leuk. Res. (2001) 25(10):917–925.
  • SAKASHITA K, KOIKE K, KINOSHITA T et al.: Dynamic DNA methylation change in the CpG island region of p15 during human myeloid development. Clin. Invest. (2001) 108(8):1195–1204.
  • MILHEM M, MAHMUD N, LAVELLE D et al: Modification of hematopoietic stem cell fate by 5aza neoxycytidine and trichostatin A. Blood (2004) 103(11):4102–4110.
  • ZOU YR, SUNSHINE MJ, TANIUCHI I, HATAM F, KILLEEN N, LITTMANN DR: Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nat. Genet. (2001) 29(3):332–336.
  • TANIUCHI I, SUNSHINE MJ, FESTENSTEIN R, LITTMANN DR: Evidence for distinct CD4 silencer functions at different stages of thymocyte differentiation. Mol Cell. (2002) 10(5):1083–1096.
  • WALSH CP, CHAILLET JR, BESTOR TH: Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. (1998) 20(2):116–117.
  • XU GL, BESTOR TH, BOURC'HIS D et al: Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature (1999) 402(6758):187–191.
  • ••Unravelling of the molecular defect inICF syndrome via mutation-induced insufficiency of both DNMT 3b alleles.
  • GAUDET F, HODGSON JG, EDEN A et al: Induction of tumors in mice by genomic hypomethylation. Science (2003) 300(5618):489–492.
  • EDEN A, GAUDET F, WAGHMARE A, JAENISCH R: Chromosomal instability and tumors promoted by DNA hypomethylation. Science (2003) 300(5618):455.
  • LENGAUER C: Cancer. An unstable liaison. Science (2003) 300(5618): 442–443.
  • YANG AS, ESTECIO MR, GARCIA-MANERO G, KANTARJIAN HM, ISSA JP: Comment on 'Chromosomal instability and tumors promoted by DNA hypomethylation' and 'Induction of tumors in mice by genomic hypomethylation'. Science (2003) 302(5648):1153.
  • PFEIFER GP, STEIGERWALD S, BOEHM TL, DRAHOVSKY D: DNA methylation levels in acute human leukemia. Cancer Lett. (1988) 39(2):185–192.
  • WAHLFORS J, HILTUNEN H, HEINONEN K, HAMALAINEN E, ALHONEN L, JANNE J: Genomic hypomethylation in human chronic lymphocytic leukemia. Blood (1992) 80(8):2074–2080.
  • LYKO F, STACH D, BRENNER A et al: Quantitative analysis of DNA methylation in chronic lymphocytic leukemia patients. Electrophoresis (2004) 25(10-11):1530–1535.
  • COSTELLO JF, FRUHWALD MC, SMIRAGLIA DJ et al.: Aberrant CpG-island methylation has non-random and tumour-type-specific patterns. Nat. Genet. (2000) 24(2):132–138.
  • ••Seminal report of global analysis of> 1000 CpG islands in 98 primary tumours by use of retriction landmark genomic scanning: proof of global methylation profiles specific for distinct tumor types.
  • RUSH LJ, DAI Z, SMIRAGLIA DJ et al: Novel methylation targets in de novo acute myeloid leukemia with prevalence of chromosome 11 loci. Blood (2001) 97(10):3226–3233.
  • •Application of restriction landmark genomic scanning in acute leukaemia: confirmation of the chromosome 11 methylation hot spot.
  • NAKAYAMA M, WADA M, HARADA T et al.: Hypomethylation status of CpG sites at the promoter region and overexpression of the human MDR1 gene in acute myeloid leukemias. Blood (1998) 92(10:4296–4307.
  • LEITH CP, KOPECKY KJ, CHEN IM et al.: Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood (1999) 94(3):1086–1099.
  • ANDO T, NISHIMURA M, OKAY: Decitabine (5-Aza-2'-deoxycytidine) decreased DNA methylation and expression of MDR-1 gene in K562/ADM cells. Leukemia (2000) 14(11):1915–1920.
  • TSUKAMOTO N, MORITA K, KARASAWA M, OMINE M: Methylation status of c-myc oncogene in leukemic cells: hypomethylation in acute leukemia derived from myelodysplastic syndromes. Exp. Hematol (1992) 20(9):1061–1064.
  • JENUWEIN T, ALLIS CD: Translating the histone code. Science (2001) 293(5532):1074–1080.
  • BANNISTER AJ, ZEGERMAN P, PARTRIDGE JF et al: Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature (2001) 410(6824):120–124.
  • ••First demonstration of heterochromatinprotein 1 binding with high affmity to H3 is dependent on specific lysine 9 methylation in yeast.
  • MERMOUD JE, POPOVA B, PETERS AH, JENUWEIN T, BROCKDORFF N: Histone H3 lysine 9 methylation occurs rapidly at the onset of random X chromosome inactivation. Curr. Biol. (2002) 12(3):247–251.
  • JAENISCH R, BIRD A: Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. (2003) 33(Suppl.):245–254.
  • HERMAN JG, BAYLIN SB: Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. (2003) 349(20:2042–2054.
  • •Excellent review integrating our present knowledge of gene silencing in neoplasia with the clinical implications for diagnosis, disease monitoring and treatment agents reverting hypermethylation.
  • CHIM CS, LIANG R, KWONG YL: Hypermethylation of gene promoters in hematological neoplasia. Hematol Oncol (2002) 20(4):167–176.
  • CLAUS R, LOBBERT M: Epigenetic targets in hematopoietic malignancies. Oncogene (2003) 22(42):6489–6496.
  • LEHMANN U, BRAKENSIEK K, KREIPE H: Role of epigenetic changes in hematological malignancies. Ann. Hematol. (2004) 83(3):137–152.
  • CHEN H, WU S: Hypermethylation of the p15(INK4B) gene in acute leukemia and myelodysplastic syndromes. ChM. Med. J. (2002) 115(7):987–90.
  • NGUYEN TT, MOHRBACHER AF, TSAI YC et al.: Quantitative measure of c-abl and p15 methylation in chronic myelogenous leukemia: biological implications. Blood (2000) 95(9)2990–2992.
  • GALM O, WILOP S, REICHELT J et al.: DNA methylation changes in multiple myeloma. Leukemia (2004) Epub ahead of print.
  • ROMAN-GOMEZ J, JIMENEZ-VELASCO A, CASTILLEJO JA et al: Promoter hypermethylation of cancer-related genes is a strong independent prognostic factor in acute lymphoblastic leukemia. Blood (2004) Epub ahead of print.
  • •Largest study to date of gene methylation In ALL being predictive for outcome.
  • GARCIA MJ, MARTINEZ-DELGADO B, CEBRIAN A, MARTINEZ A, BENITEZ J, RIVAS C: Different incidence and pattern of pl5INK4b and pl6INK4a promoter region hypermethylation in Hodgkin's and CD30-positive non-Hodgkin's lymphomas. Am. J. Pathol (2002) 161(3):1007–1013.
  • NAGY E, BECK Z, KISS A et al: Frequent methylation of pl 6INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase. Eur. Cancer (2003) 39(16):2298–2305.
  • GUO SX, TAKI T, OHNISHI H et al: Hypermethylation of p16 and p15 genes and RB protein expression in acute leukemia. Leuk. Res. (2000) 24(1):39–46.
  • MATSUSHITA C, YANG Y, TAKEUCHI S et al: Aberrant methylation in promoter-associated CpG islands of multiple genes in relapsed childhood acute lymphoblastic leukemia. Oncol Rep. (2004) 12(1):97–99.
  • 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 13 (RAR 13) promoter and restores retinoid responsiveness in non M3 acute myelogenous leukemia (AML) blasts. Blood (2001) 98(Suppl.):460a.
  • SEIDL S, ACKERMANN J, KAUFMANN H et al.: DNA-methylation analysis identifies the E-cadherin gene as a potential marker of disease progression in patients with monoclonal gammopathies. Cancer (2004) 100(12):2598–2606.
  • CHIM CS, KWONG YL, FUNG TK, LIANG R: Methylation profiling in multiple myeloma. Leuk. Res. (2004) 28(4):379–385.
  • SIU LL, CHAN JK, WONG KF, CHOY C, KWONG YL: Aberrant promoter CpG methylation as a molecular marker for disease monitoring in natural killer cell lymphomas. Br. J. Haematol. (2003) 122 (1) :70–77.
  • ISSA JP, ZEHNBAUER BA, CIVIN CI et al.: The estrogen receptor CpG island is methylated in most hematopoietic neoplasms. Cancer Res. (1996) 56(5)973–977.
  • •First report demonstrating the high incidence of ER methylation in leukaemia.
  • VOSO MT, SCARDOCCI A, GUIDI F et al.: Aberrant methylation of DAP-kinase in therapy-related acute myeloid leukemia and myelodysplastic syndromes. Blood (2004) 103(2):698–700.
  • ROSSI D, CAPELLO D, GLOGHINI A et al.: Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia. Haematologica (2004) 89(2):154–164.
  • MARTINEZ-DELGADO B, MELENDEZ B, CUADROS Metal.: Frequent inactivation of the p73 gene by abnormal methylation or LOH in non-Hodgkin's lymphomas. Int. J. Cancer (2002) 102(1):15–19.
  • CORN PG, SMIH BD, RUCKDESCHEL ES, DOUGLAS D, BAYLIN SB, HERMAN JG: E-cadherin expression is silenced by 5' CpG island methylation in acute leukemia. Clin. Cancer Res. (2000) 6(11):4243–4248.
  • ROMAN-GOMEZ J, CASTILLEJO JA, JIMENEZ A et al.: Cadherin-13, a mediator of calcium-dependent cell-cell adhesion, is silenced by methylation in chronic myeloid leukemia and correlates with pretreatment risk profile and cytogenetic response to interferon alfa. Clin. Oncol. (2003) 21(8):1472–1479.
  • OGAMA Y, OUCHIDA M, YOSHINO T et al: Prevalent hyper-methylation of the CDH13 gene promoter in malignant B cell lymphomas. Lit. Oncol. (2004) 25(3):685–691.
  • TAKAHASHI T, SHIVAPURKAR N, REDDY J et al.: DNA methylation profiles of lymphoid and hematopoietic malignancies. Clin. Cancer Res. (2004) 10(9):2928–2935.
  • ISSA JP, BAYLIN SB, HERMAN JG: DNA methylation changes in hematologic malignancies: biologic and clinical implications. Leukemia (1997) 11 (Suppl.):7–11.
  • MIZUNO S, CHIJIWA T, OKAMURA K et al.: Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood (2001) 97(5):1172–1179.
  • AOKI E, OHASHI H, UCHIDA T, MURATE T, SAITO H, KINOSHITA T: Expression levels of DNA methyltransferase genes do not correlate with p15INK4B gene methylation in myelodysplastic syndromes. Leukemia (2003) 17(9):1903–1904.
  • NGUYEN CT, GONZALES FA, JONES PA: Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation. Nucleic. Acids. Res. (2001) 29(22):4598–4606.
  • •Comprehensive analysis of the p16 promoter status as modified epigenetically in bladder cancer cells.
  • 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(5557):1079–1082.
  • ••First report linking genetic events inleukaemia subtype (APL with PML-RARa rearrangement) and epigenetic alteration (methylation silencing of the RAR0 target gene of PML-RAR) via DNMT 3a.
  • WIDSCHWENDTER M, BERGER J, HERMANN M et al.: Methylation and silencing of the retinoic acid receptor-beta2 gene in breast cancer. J. Nati Cancer Inst. (2000) 92(10):826–832.
  • •This paper underscores the role of RAR silencing in solid tumors and its clinical implications.
  • FERRARA FE FAZI F, BIANCHINI A et al.: Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res. (2001) 61(1):2–7.
  • MINUCCI S, NERVI C, LO CE PELICCI PG: Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias? Oncogene (2001) 20(24):3110–3115.
  • LIU S, SHEN T, RUSH LJ et al.: AML1/ETO Associates with DNA methyltransferase 1 (DNMT1) in inducing transcriptional repression of the AML1-target gene interleukin-3 (IL-3). Blood (2003) 102(Abstr.):218a.
  • KLISOVIC MI, MAGHRABY EA, PARTHUN MR et al.: Depsipeptide (FR 901228) promotes histone acetylation, gene transcription, apoptosis and its activity is enhanced by DNA methyltransferase inhibitors in AML1/ETO-positive leukemic cells. Leukemia (2003) 17(2):350–358.
  • •Seminal report of the co-operation of an HDAC inhibitor and DNMT inhibitor on the AML1/ETO model of gene silencing by de-repression of the IL-3 gene.
  • WONG IH, NG MH, HUANG DP, LEE JC: Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood (2000) 95(6):1942–1949.
  • TOYOTA M, KOPECKY KJ, TOYOTA MO, JAIR KW, WILLMANN CL, ISSA JP: Methylation profiling in acute myeloid leukemia. Blood (2001) 97(9):2823–2829.
  • •First report of methylation profiling covering a broad spectrum of genes in AML.
  • LOBBERT M: Gene silencing of the p15/INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes? Leukemia (2003) 17(9):1762–1764.
  • HERMAN JG, JEN J, MERLO A, BAYLIN SB: Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. (1996) 56(4):722–727.
  • ••This paper defines p15 methylationas a major epigenetic event equivalent to deletions and point mutations in primary cancers.
  • HERMAN JG, CIVIN CI, ISSA JP, COLLECTOR MI, SHARKIS SJ, BAYLIN SB: Distinct patterns of inactivation of p15INK4B and pl6INK4A characterize the major types of hematological malignancies. Cancer Res. (1997) 57(5):837–841.
  • DREXLER HG: Review of alterations ofthe cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells. Leukemia (1998) 12(6):845–859.
  • MELKI JR, VINCENT PC, CLARK SJ: Concurrent DNA hypermethylation of multiple genes in acute myeloid leukemia. Cancer Res. (1999) 59(15):3730–3740.
  • •Demonstration and structural analysis of multiple hypermethylation events in leukaemia.
  • RANDHAWA GS, CUI H, BARLETTA JA et al.: Loss of imprinting in disease progression in chronic myelogenous leukemia. Blood(1998) 91(9):3144–3147.
  • VORWERK P, WEX H, BESSERT C, HOHMANN B, SCHMIDT U, MITTLER U: Loss of imprinting of IGF-II gene in children with acute lymphoblastic leukemia. Leuk. Res. (2003) 27(9):807–812.
  • WU HK, WEKSBERG R, MINDEN MD, SQUIRE JA: Loss of imprinting of human insulin-like growth Factor II gene, IGF2, in acute myeloid leukemia. Biochem. Biophys. Res. Commun. (1997) 231(2):466–472.
  • BELINSKY SA, NIKULA KJ, PALMISANO WA et al.: Aberrant methylation of p16(INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc. Nati Acad. Sci. USA (1998) 95(20):11891–11896.
  • •Lung cancer as a model disease for methylation being an epigenetic event was demonstrated to be a ssessable to early diagnosis by the tool of methylation analysis.
  • ESTELLER M, GARCIA-FONCILLAS J, ANDION E et al.: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl. J. Med. (2000) 343(19):1350–1354.
  • •Impressive correlative study of the predictive value of gene silencing and chemotherapy sensitivity or resistance In the glioma model.
  • PLASS C, YU F, YU L et al.: Restriction landmark genome scanning for aberrant methylation in primary refractory and relapsed acute myeloid leukemia; involvement of the WIT-1 gene. Oncogene (1999) 18(20):3159–3165.
  • 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.
  • •Second report defining p15 as a frequent target of hypermethylation in MDS, with a correlation with blast expansion.
  • CHIM CS, TAM CY, LIANG R, KWONG YL: Methylation of p15 and p16 genes in adult acute leukemia: lack of prognostic significance. Cancer (2001) 91(12):2222–2229.
  • CHRISTIANSEN DH, ANDERSEN MK, PEDERSEN-BJERGAARD J: Methylation of pl5INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia. Leukemia (2003) 17(9):1813–1819.
  • CHEN W, WU Y, ZHU J, LIU J, TAN S, XIA C: Methylation of p16 and p15 genes in multiple myeloma. Chin. Med. Sci. I (2002) 17(2):101–105.
  • AU WY, FUNG A, MAN C et al.: Aberrant p15 gene promoter methylation in therapy-related myelodysplastic syndrome and acute myeloid leukaemia: clinicopathological and karyotypic associations. BE J. Haematol. (2003) 120(6):1062–1065.
  • JONES PA, TAYLOR SM: Cellular differentiation, cytidine analogs and DNA methylation. Cell (1980) 20 (1) :85–93.
  • ••This paper provided the basis fordemethylating therapy with azanucleosides in cancer, leukaemia and haemoglobinopathy.
  • CONSTANTINIDES PG, JONES PA, GEVERS W: Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment. Nature (1977) 267(5609):364–366.
  • ••First discovery of the differentiation-inducing capacity of an azanudeoside, leading to the discovery of methylation inhibition to this compound and its sister compound 5-aza-2--deoxycytidine.
  • CREUSOT F, ACS G, CHRISTMAN JK: Inhibition of DNA methyltransferase and induction of Friend erythroleukemia cell differentiation by 5-azacytidine and 5-aza-2'-deoxycytidine. "Biol.Chem. (1982) 257(4):2041–2048.
  • CHENG JC, MATSEN CB, GONZALES FA: Inhibition of DNA methylation and reactivation of silenced genes by zebularine. J. Natl. Cancer Inst. (2003) 95(5):399–409.
  • •Zebularine is the first DNA methylation Inhibitor being orally available.
  • VILLAR-GAREA A, FRAGA ME ESPADA J, ESTELLER M: Procaine is a DNA-demethylating agent with growth-inhibitory effects in human cancer cells. Cancer Res. (2003) 63(16):4984–4989.
  • •Procaine and other compounds provide a novel demethylating activity without the incorporation into DNA.
  • FANG MZ, WANG Y, Al N: Tea polyphenol O-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. (2003) 63(22):7563–7570.
  • LEVI JA, WIERNIK PH: A comparative clinical trial of 5-azacytidine and guanazole in previously treated adults with acute nonlymphocytic leukemia. Cancer (1976) 38(1):36–41.
  • LOBBERT 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.
  • •Comprehensive review of preclinical models and clinical applications of demethylating therapy in hematology.
  • SANTINI V, KANTARJIAN HM, ISSA JP: Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann. Intern. Med. (2001) 134(7):573–586.
  • •A review of the application of demethylating agents in hematological neoplasia and solid tumors.
  • 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.
  • •Important Phase II study of the CALGB demonstrating the clinically meaningful effects of low-dose 5-AZA treatment in MDS.
  • RUGO HS, DAMON L, RIES C, LINKER C: Compassionate use of subcutaneous 5-azacytidine (azaC) in the
  • •• treatment of myelodysplastic syndromes (MDS). Leuk. Res. (1999) 23\(Suppl. 1):72.
  • SILVERMAN LR, HOLLAND JF, DEMAKOS EP et al: Azacytidine (AzaC) in myelodysplastic syndromes (MDS), CALGB Studies 8421 and 8921. Ann Hematol (1994) 68\(Suppl. 2):21a.
  • SHADDUCK RK, LISTER J, RAYMOND JM, ZEIGLER ZR: 5-azacytidine therapy for myelodysplasia. Leuk. Res. (1999) 23\(Suppl. 1):72.
  • GRYN J, ZEIGLER ZR, SHADDUCK RK et al.: Treatment of myelodysplastic syndromes with 5-azacytidine. Leuk. Res. (2002) 26(10):893–897.
  • SILVERMAN LR, DEMAKOS EP, PETERSON BL 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.
  • ••Pivotal study of 5-AZA in MDS:the first report of non-intensive treatment changing the natural course of myelodysplasia.
  • 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, LOBBERT M, VERHOEF G et al: Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter Phase II study in elderly patients. ./. Clin. Oncol (2000) 18(5):956–962.
  • •The significant response rate of low-dose decitabine in 66 elderly patients treated in a multicenter trial demonstrates remarkable single-agent activity of this approach.
  • WIJERMANS PW, LOBBERT M, VERHOEF G: Low dose decitabine for elderly high risk MDS patients: who will respond? Blood (2002) 100:96a.
  • ISSA JP, GARCIA-MANERO G, GILES FJ et al.: Phase I study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood (2004) 103(5):1635–1640.
  • •Issa and co-workers compared different total doses and durations of low-dose decitabine and, interestingly, highest activity in a lower dose range.
  • KARON M, SIEGER L, LEIMBROCK S, FINKLESTEIN JZ, NESBIT ME, SWANEY JJ: 5-Azacytidine: a new active agent for the treatment of acute leukemia. Blood (1973) 42(3):359–365.
  • VON HOFF DD, SLAVIK M, MUGGIA FM: 5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia. Ann. Intern. Med. (1976) 85(2):237–245.
  • •A broad overview of the experience with 5-AZA accumulated until 1976.
  • SAIKI JH, MCCREDIE KB, VIETTI TJ et al.: 5-azacytidine in acute leukemia. Cancer (1978) 42(5):2111–2114.
  • OMURA GA, VOGLER WR, BARTOLUCCI A, NEELY CL, SILBERMAN H: Treatment of refractory adult acute leukemia with 5-azacytidine plus beta-2'-deoxythioguanosine. Cancer Treat Rep. (1979) 63(2):209–211.
  • WINTON EF, HEARN EB, MARTELO O et al: Sequentially administered 5-azacitidine and amsacrine in refractory adult acute leukemia: a Phase I-II trial of the Southeastern Cancer Study Group. Cancer Treat. Rep. (1985) 69(7-8):807–811.
  • DUTCHER JP, EUDEY L, WIERNIK PH et al.: Phase II study of mitoxantrone and 5-azacytidine for accelerated and blast crisis of chronic myelogenous leukemia: a study of the Eastern Cooperative Oncology Group. Leukemia (1992) 6(8):770–775.
  • GOLDBERG J, GRYN J, RAZA A et al: Mitoxantrone and 5-azacytidine for refractory/relapsed ANLL or CML in blast crisis: a leukemia intergroup study. Am. J. Hematol (1993) 43(4):286–290.
  • 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.
  • •This pioneering study demonstrated good tolerability and remarkable responses in an elderly patient population.
  • ZAGONEL V, PINTO A, BULLIAN PL et al: 5-Aza-2'-deoxycytidine as a differentiation inducer in human hematopoietic malignancies. In: 5-Aza-2'-deoxycytidine: preclinical and clinical studies. Momparler RL, De Vos D(Eds), PCH, Haarlem, The Netherlands (1990):165–181.
  • DEBUSSCHER L, MARIE JP, DODION P et al: Phase-I-II trial of 5-aza-2" deoxycytidine in adult patients with acute leukemia. In: 5-Aza-2'-deoxycytidine: preclinical and clinical studies. Momparler RL, De Vos D (Eds), PCH, Haarlem, The Netherlands (1990):131–142.
  • KANTARJIAN HM, O'BRIEN SM, KEATING M et al.: Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia. Leukemia (1997) 11(10):1617–1620.
  • WILLEMZE R, SUCIU S, ARCHIMBAUD E et al: A randomized Phase II study on the effects of 5-Aza-2'-deoxycytidine combined with either amsacrine or idarubicin in patients with relapsed acute leukemia: an EORTC Leukemia Cooperative Group Phase II study (06893). Leukemia (1997) 11 (Suppl. 1):24–27.
  • SACCHI S, KANTARJIAN HM, O'BRIEN S et al: Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients. Cancer (1999) 86(12):2632–2641.
  • KANTARJIAN HM, O'BRIEN S, CORTES J et al.: Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer (2003) 98(3)522–528.
  • PINTO A, ATTADIA V, FUSCO A, FERRARA F, SPADA OA, DI FIORE PP: 5-Aza-2'-deoxycytidine induces terminal differentiation of leukemic blasts from patients with acute myeloid leukemias. Blood (1984) 64(4):922–929.
  • •Ex vivo differentiation of some leukaemias after incubation with decitabine served as the rational for low-dose treatment with this group of drugs as differentiation therapy.
  • PETTI MC, MANDELLI F, ZAGONEL V et al: Pilot study of 5-aza-2'-deoxycytidine (Decitabine) in the treatment of poor prognosis acute myelogenous leukemia patients: preliminary results. Leukemia (1993) 7\(Suppl. 1):36–41.
  • LOBBERT M, WIJERMANS P, KUNZMANN R et al: Cytogenetic responses in high-risk myelodysplastic syndrome following low-dose treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine. BE J. Haematol(2001) 114(2):349–357.
  • •Low-dose azanudeosides can induce complete cytogenetic normalisation that appears even more frequently in the high-risk than in the intermediate-risk cytogenetic subgroup, and is associated with significantly longer survival.
  • DASKALAKIS M, NGUYEN TT, NGUYEN C et al.: Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2'-deoxycytidine (decitabine) treatment. Blood (2002) 100(8):2957–2964.
  • •First demonstration of in vivo demethylation of a gene hypermethylated in a clonal haematologic disorder.
  • ISSA JP, GARCIA-MANERO G, MANNARI R et al.: Minimal effective dose of hypomethylating agent decitabine in hematopoietic malignancies. Blood (2001) 98\(Suppl. 1):594a.
  • MILLER CB, HERMAN JG, BAYLIN SB, GALM O, YERIAN JA, GORE SD: A Phase I dose-descalation trial of combined DNA methyltransferase (IVIeT)/histone deacetylase (HDAC) inhibition in myeloid malignancies. Blood (2001) 98\(Suppl. 1):622a.
  • SIGALOTTI L, ALTOMONTE M, COLIZZI F et al: 5-Aza-2'-deoxycytidine (decitabine) treatment of hematopoietic malignancies: a multimechanism therapeutic approach? Blood (2003) 101(11):4644–4646.
  • •Cancer-testis-antigens are upregulated in their expression in vivo.
  • MAIO M, CORAL S, FRATTA E, ALTOMONTE M, SIGALOTTI L: Epigenetic targets for immune intervention in human malignancies. Oncogene (2003) 22 (42):6484–6488.
  • APARICIO A, WEBER JS: Review of the clinical experience with 5-azacytidine and 5-aza-2'-deoxycytidine in solid tumors. Curl: Opia Investig. Drugs (2002) 3(4):627–633.
  • HENNESSY BT, GARCIA-MANERO G, KANTARJIAN HM, GILES FG: DNA methylation in haematological malignancies: the role of decitabine. Expert. Opia Investig. Drugs (2003) 12(12):1985–1993.
  • DESIMONE J, HELLER P, HALL L, ZWIERS D: 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Five. Natl. Acad. Sci. USA (1982) 79(14):4428–4431.
  • LEY TJ, DESIMONE J, ANAGNOU NP et al: 5-azacytidine selectively increases gamma-globin synthesis in a patient with beta+ thalassemia. N Engl. I Med. (1982) 307(24):1469–1475.
  • ••The seminal report of a first patientwith haemoglobinopathy responding to an azanucleoside by increased y-globin synthesis.
  • DOVER GJ, CHARACHE SH, BOYER SH, TALBOT CCJ, SMITH KD: 5-Azacytidine increases fetal hemoglobin production in a patient with sickle cell disease. Frog. Clin. Biol. Res. (1983) 134:475–488.
  • KOSHY M, DORN L, BRESSLER L et al.: 2-deoxy 5-azacytidine and fetal hemoglobin induction in sickle cell anemia. Blood (2000) 96(7):2379–2384.
  • 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 (12) :3865–3870.
  • •Comprehensive study of the clinical and biological effects of continued treatment with azanucleosides in sickle cell disease refractory to hydroxyurea.
  • WATSON J, STALDMAN AW, BILELLO FP: The significance of the paucity of sickle cells in newborn negro infants. Am. J. Med. Sci. (1948) 215:419–423
  • GARBER K: Silence of the genes: cancer epigenetics arrives. J. Natl. Cancer Inst. (2002) 94(11)793–795.
  • WARRELL RPJ, HE LZ, RICHON V, CALLEJA E, PANDOLFI PP: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J. Natl. Cancer Inst. (1998) 90(20:1621–1625.
  • ••First report of clinical remission followingHDAC inhibitor treatment in refractory leukaemia.
  • GOTTLICHER M, MINUCCI S, ZHU P et al: Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J. (2001) 20(24):6969–6978.
  • •VPA, a drug of longstanding use, is being rediscovered for its inhibitory effect on HDACs.
  • PHIEL CJ, ZHANG F, HUANG EY, GUENTHER MG, LAZAR MA, KLEIN PS: Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol. Chem. (2001) 276(39):36734–36741.
  • •Simultaneous discovery, as in [143].
  • GORE SD, WENG LJ, ZHAI S et al.: Impact of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin. Cancer Res. (2001) 7(8):2330–2339.
  • •Carefully conducted clinical trial with the classic HDAC inhibitor, sodiumphenylbutyrate, in haematological neoplasia.
  • PIEKARZ RL, ROBEY R, SANDOR V et al.: Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. Blood (2001) 98(9):2865–2868.
  • KELLY WK, RICHON VM, O'CONNOR O eta].: Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. Clin. Cancer Res. (2003) 9(10 pt1):3578–3588.
  • KUENDGEN A, STRUPP C, AIVADO M et al.: Treatment of myelodysplastic syndromes with valproic acid alone or in combination with all-trans retinoic acid. Blood (2004) 104(5):1266–1269.
  • •Very recent report of remarkable activity of VPA in MDS.
  • 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(1):103–107.
  • ••The synergism between inhibitors ofmethylation and of histone deacetylation provide the signposts to the exploration of clinical application of these two groups of drugs in combination trials.
  • LEMAIRE M, MOMPARLER LF, FARINHA NJ, BERNSTEIN M, MOMPARLER RL: Enhancement of antineoplastic action of 5-aza-2'-deoxycytidine by phenylbutyrate on L1210 leukemic cells. Leuk. Lymphoma (2004) 45(1):147–154.
  • CAMACHO LH, RYAN J, CHANEL S et al.: Transcription modulation: a pilot study of sodium phenylbutyrate plus 5-azacytidine. Blood (2001) 98 (Suppl.):460a.
  • KAWASAKI H, TAIRA K: Induction of DNA methylation and gene silencing by short interfering RNAs in human cells. Nature (2004) 431(7005):211–217.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.