DNA METHYLTRANSFERASE 1 (DNMT1) GENE ACTIVITY IN HUMAN LYMPHOMAS CORRELATES WITH ABERRANT p53 GENE EXPRESSION

Authors

  • Iftikhar Qayum
  • Muhammad Ashraf

Abstract

Background: The DNA Methyltransferase 1 (DNMT1) gene has been implicated as a mutagen
for tumor suppressor genes by causing hypermethylation and subsequent TA mutations of CpG
islands located in the promoter regions of these genes. The present study was undertaken to
determine if increased DNMT1 gene activity correlated with increased aberrant p53 gene
expression in human lymphomas. Methods: The study was undertaken on randomly selected
archival human lymph nodes comprising 50 normal or reactive lymph nodes and 50 lymphoma
lymph nodes. These were subjected to Fluorescent In Situ Hybridization (FISH) using
oligonucleotide Antisense probes for the DNMT1 and the p53 mRNA according to standard FISH
protocols. Percent cells stained, mean '˜dots' stained per cell and staining signal intensity were
taken as the criteria for comparing control and lymphoma lymph nodes. Quantitation of probe
signals was done both by manual visualization of fluorescent signals and computer based image
analysis. Correlation analysis was performed by calculation of Pearson's correlation coefficient.
Results: Data indicated significantly increased expression of the DNMT1 and the p53 mRNA in
lymphoma cases as compared to controls (p<0.001). Moreover significant correlation was
obtained for the expressions of these two genes in lymphomas (p<0.001), but not in control lymph
nodes. Conclusion: Increased DNMT1 gene activity may contribute to increased p53 gene
expression in human lymphomas, supporting a mutagenic role for the DNMT1 gene.
Key Words: Fluorescent In Situ Hybridization, p53, DNA Methyltransferases, lymphomas.

References

Lapeyre JN, Becker FF. 5-Methylcytosine content of nuclear

DNA during chemical hepatocarcinogenesis and in

carcinomas which result. Biochem Biophys Res Commun

; 87: 698-705.

Gama-Sosa MA, Slagel VA, Trewyn RW, Oxenhandler R,

Kuo KC, Gehrke CW et al. The 5-Methylcytosine content of

DNA from human tumors. Nucleic Acids Res 1983; 11:

-94.

Feinberg AP, Gehrke CW, Kuo KC, Ehrlich M. Reduced

genomic 5-methylcytosine content in human colonic

neoplasia. Cancer Res 1988; 48: 1159-61.

Bird A, Tate P, Nan X, Campoy J, Meehan R, Cross S et al.

Studies of DNA methylation in animals. J Cell Sci Suppl

; 19: 37-9.

Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP.

Alterations in DNA methylation: a fundamental aspect of

neoplasia. Adv Cancer Res 1998: 72: 141-96.

Baylin SB, Fearon ER, Vogelstein B, deBustros A, Sharkis

SJ, Burke PJ et al. Hypermethylation of the 5' region of the

calcitonin gene is a property of human lymphoid and acute

myeloid malignancies. Blood 1987; 70: 412-7.

Kautiainen TL, Jones PA. DNA methyltransferase levels in

tumorigenic and nontumorigenic cells in culture. J Biol Chem

; 261: 1594-8.

Issa JP, Baylin SB, Herman JG. DNA methylation changes in

hematologic malignancies: biologic and clinical implications.

Leukemia 1997; 11 (Suppl 1): S7-11.

J Ayub Med Coll Abbottabad 2006;18(1)

Melki JR, Warnecke P, Vincent PC, Clark SJ. Increased

DNA methyltransferase expression in leukaemia. Leukemia

; 12(3): 311-6.

Herman JG. Hypermethylation of tumor suppressor genes in

cancer. Semin Canc Biol 1999; 9: 359-67.

Herman JG, Baylin SB. Promoter-region hypermethylation

and gene silencing in human cancer. Curr Top Microbiol

Immunol 2000; 249: 35-54.

Jones PA. DNA methylation errors and cancer. Cancer Res

; 56: 2643-67.

Wachsman JT. DNA methylation and the association

between genetic and epigenetic changes: relation to

carcinogenesis. Mut Res 1997; 375: 1-8.

Issa JP, Baylin SB, Herman JG. DNA methylation changes in

hematologic malignancies: biologic and clinical implications.

Leukemia 1997; 11 Suppl 1: S7-11.

Batova A, Diccianni MB, Yu JC, Nobori T, Link MP, Pullen

J et al. Frequent and selective methylation of p15 and

deletion of both p15 and p16 in T-cell acute lymphoblastic

leukemia. Cancer Res 1997; 57(5): 832-6.

Dodge JE, List AF, Futscher BW. Selective variegated

methylation of the p15 CpG island in acute myeloid

leukemia. Int J Cancer 1998; 78(5): 561-7.

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(6):

-59.

Martinez-Delgado B, Robledo M, Arranz E, Osorio A,

Garcia MJ, Echezarreta G et al. Hypermethylation of

p15/ink4b/MTS2 gene is differentially implicated among

non-Hodgkin's lymphomas. Leukemia 1998; 12(6): 937-41.

Aggerholm A, Guldberg P, Hokland M, Hokland P.

Extensive intra- and inter- individual heterogeneity of

p15INK4B methylation in acute myeloid leukemia. Cancer

Res 1999; 59(2): 436-41.

Moller MB, Ino Y, Gerdes AM, Skjodt K, Louis DN,

Pedersen NT. Aberrations of the p53 pathway components

p53, MDM2 and CDKN2A appear independent in diffuse

large B cell lymphoma. Leukemia 1999; 13(3): 453-9.

Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M,

Compitello N, Baylin SB et al. Transcriptional silencing of

the p73 gene in acute lymphoblastic leukemia and Burkitt's

lymphoma is associated with 5' CpG island methylation.

Cancer Res 1999; 59(14): 3352-6.

Kawano S, Miller CW, Gombart AF, Bartram CR, Matsuo Y,

Asou H et al. Loss of p73 gene expression in leukemias /

lymphomas due to hypermethylation. Blood 1999; 94(3):

-20.

Crossen PE, Morrison MJ. Methylation status of the 3rd exon

of the c-MYC oncogene in B-cell malignancies. Leuk Res

; 23(3): 251-3.

Nakamura M, Sugita K, Inukai T, Goi K, Iijima K, Tezuka T

et al. p16/MTS1/INK4A gene is frequently inactivated by

hypermethylation in childhood acute lymphoblastic leukemia

with 11q23 translocation. Leukemia 1999; 13(6): 884-90.

Lewin B. Genes V. 1st ed., New York USA: Oxford

University Press. 1994.

Lutsenko E, Bhagwat AS. Principal causes of hot spots for

cytosine to thymine mutations at sites of cytosine

methylation in growing cells. A model, its experimental

support and implications. Mutat Res 1999; 437(1): 11-20.

Warnecke PM, Bestor TH. Cytosine methylation and human

cancer. Curr Opin Oncol 2000; 12: 68-73.

Hainaut P, Hernandez T, Robinson A, Rodriguez-Tome P,

Flores T, Hollstein M et al. IARC database of p53 gene

mutations in human tumors and cell lines: updated

compilation, revised formats and new visualisation tools.

Nucleic Acids Res 1998; 26: 205-13.

Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J,

Gonzales FA et al. The human DNA methyltransferases

(DNMTs) 1, 3a and 3b: coordinate mRNA expression in

normal tissues and over expression in tumors. Nucleic Acids

Res 1999; 27: 2291-8.

Robertson KD, Wolffe AP. DNA methylation in health and

disease. Nat Rev Genet 2000; 1: 11-9.

Sutherland JE, Costa M. DNA methylation and gene

silencing. In: Heuvel JPV, Perdew GH, Mattes WB, Greenlee

WF (Eds.). Comprehensive Toxicology, vol xiv, Somerset

UK: Elsevier Science BV 2002. pp 299-310.

Bakin AV, Curran T. Role of DNA 5-methylcytosine

transferase in cell transformation by fos. Science 1999; 283:

-90.

Issa JP, Vertino PM, Wu J, Sazawal S, Celano P, Nelkin BD

et al. Increased cytosine DNA-methyltransferase activity

during colon cancer progression. J Nat Cancer Inst 1993; 85:

-40.

Qayum I, Ashraf M. Increased DNA Methyltransferase 1

(DNMT1) gene activity in human lymphomas by Fluorescent

In Situ Hybridization. J Ayub Med Coll Abbottabad 2004;

(4): 1-6.

Lehr HA, Jacobs TW, Yaziji H, Schnitt SJ, Gown AM.

Quantitative evaluation of HER-2/neu status in breast cancer

by Fluorescence In Situ Hybridization and by

immunohistochemistry with image analysis. Am J Clin

Pathology 2001; 115(6): 814-22. Available from:

http://www.medscape.com/ASCP/AJCP/2001/v115.n06/ajcp

02.lehr/ajcp1156.02.lehr-01.html

Finlay CA, Hinds PW, Levine AJ. The p53 proto-oncogene

can act as a suppressor of transformation. Cell 1989; 57:

-93.

Watson JD, Gilman M, Witkowski J, Zoller M. Recombinant

DNA. 2nd ed., New York USA: W. H. Freeman and Co. 1992.

Chen Y, Xiang Z, Li H, Yang N, Zhang H. (1999). P53 gene

mutations in non-Hodgkin's lymphoma. J Tongji Med Univ

(1): 27-30.

Klumb CE, de Resende LM, Tajara EH, Bertelli EC,

Rumjanek VM, Maia RC. p53 gene analysis in childhood B

non-Hodgkin's lymphoma. Sao Paulo Med J 2001; 119(6):

-5.

Llanos M, Alvarez-Arguelles H, Aleman R, Oramas J, DiazFlores L, Batista N. Prognostic significance of Ki-67 nuclear

proliferative antigen, bcl-2 protein, and p53 expression in

follicular and diffuse large B-cell lymphoma. Med Oncol

; 18(1): 15-22.

Naresh KN, Banavali SD, Bhatia KG, Magrath I, Soman CS,

Advani SH. Expression of P53 and bcl-2 proteins in T-cell

lymphoblastic lymphoma: prognostic implications. Leuk

Lymphoma 2002; 43(2): 333-7.

Hatta Y, Koeffler HP. Role of tumor suppressor genes in the

development of adult T cell leukemia/lymphoma (ATLL).

Leukemia 2002; 16(6):1069-85.

Moller MB, Nielsen O, Pedersen NT. Frequent alteration of

MDM2 and p53 in the molecular progression of recurring

non-Hodgkin's lymphoma. Histopathology 2002; 41(4): 322-

Garcia JF, Camacho FI, Morente M, Fraga M, Montalban C,

Alvaro T et al (Spanish Hodgkin Lymphoma Study Group).

Hodgkin and Reed-Sternberg cells harbor alterations in the

major tumor suppressor pathways and cell-cycle checkpoints:

analyses using tissue microarrays. Blood 2003; 101(2):681-9.

Epub 2002 Sep 12.

Qi ZL, Zhao T, Zhou XH, Zhang JH, Han XQ, Zhu MG.

Expressions of latent membrane protein 1, p53 and bcl-2

proteins and their significance in Hodgkin's lymphoma. Di Yi

Jun Yi Da Xue Xue Bao 2003; 23(3):225-7.

Nickenig C, Lang NK, Schoch C, Hiddemann W, Haferlach

T. New insights into the biology of multiple myeloma using a

combination of May-Grunwald-Giemsa staining and

fluorescence in situ hybridization techniques at the single cell

level. Ann Hematol 2001; 80(11): 662-8.

J Ayub Med Coll Abbottabad 2006;18(1)

Pruneri G, Carboni N, Baldini L, Intini D, Colombi M,

Bertolini F et al. Cell cycle regulators in multiple myeloma:

prognostic implications of p53 nuclear accumulation. Hum

Pathol 2003; 34(1): 41-7.

Ortega MM, Melo MB, De Souza CA, Lorand-Metze I, Costa

FF, Lima CS. A possible role of the P53 gene deletion as a

prognostic factor in multiple myeloma. Ann Hematol 2003;

(7): 405-9.

Ichikawa A. Prognostic and predictive significance of p53

mutation in aggressive B-cell lymphoma. Int J Hematol 2000;

(3): 211-20.

Stokke T, Galteland E, Holte H, Smedshammer L, Suo Z,

Smeland EB et al. Oncogenic aberrations in the p53 pathway

are associated with a high S phase fraction and poor patient

survival in B-cell Non-Hodgkin's lymphoma. Int J Cancer

; 89(4): 313-24.

Ansorena E, Garcia-Trevijano ER, Martinez-Chantar ML,

Huang ZZ, Chen L, Mato JM et al. S-adenosylmethionine

and methylthioadenosine are antiapoptotic in cultured rat

hepatocytes but proapoptotic in human hepatoma cells.

Hepatology 2002; 35(2): 274-80.

Pascale RM, Simile MM, De Miglio MR, Feo F.

Chemoprevention of hepato-carcinogenesis: S-adenosyl-Lmethionine. Alcohol 2002; 27(3): 193-8.

Villar-Garea A, Esteller M. DNA demethylating agents and

chromatin-remodelling drugs: which, how and why? Curr

Drug Metab 2003; 4(1): 11-31.

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How to Cite

Qayum, I., & Ashraf, M. (2006). DNA METHYLTRANSFERASE 1 (DNMT1) GENE ACTIVITY IN HUMAN LYMPHOMAS CORRELATES WITH ABERRANT p53 GENE EXPRESSION. Journal of Ayub Medical College Abbottabad, 18(1). Retrieved from https://www.jamc.ayubmed.edu.pk/jamc/index.php/jamc/article/view/4218

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