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Science 18 April 2003:
Vol. 300. no. 5618, pp. 489 - 492
DOI: 10.1126/science.1083558
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Reports

Induction of Tumors in Mice by Genomic Hypomethylation

François Gaudet,1,2,3 J. Graeme Hodgson,4 Amir Eden,1 Laurie Jackson-Grusby,1 Jessica Dausman,1 Joe W. Gray,4 Heinrich Leonhardt,2,3 Rudolf Jaenisch1*

Genome-wide DNA hypomethylation occurs in many human cancers, but whether this epigenetic change is a cause or consequence of tumorigenesis has been unclear. To explore this phenomenon, we generated mice carrying a hypomorphic DNA methyltransferase 1 (Dnmt1) allele, which reduces Dnmt1 expression to 10% of wild-type levels and results in substantial genome-wide hypomethylation in all tissues. The mutant mice were runted at birth, and at 4 to 8 months of age they developed aggressive T cell lymphomas that displayed a high frequency of chromosome 15 trisomy. These results indicate that DNA hypomethylation plays a causal role in tumor formation, possibly by promoting chromosomal instability.

1 Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
2 Ludwig Maximilians University, Department of Biology II, 80336 Munich, Germany.
3 Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
4 Department of Laboratory Medicine and UCSF Comprehensive Cancer Center, University of California, 2340 Sutter Street, San Francisco, CA 94143, USA.

* To whom correspondence should be addressed. E-mail: jaenisch{at}wi.mit.edu

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Epigenetic Reactivation of Tumor Suppressor Genes by a Novel Small-Molecule Inhibitor of Human DNA Methyltransferases.
B. Brueckner, R. Garcia Boy, P. Siedlecki, T. Musch, H. C. Kliem, P. Zielenkiewicz, S. Suhai, M. Wiessler, and F. Lyko (2005)
Cancer Res. 65, 6305-6311
   Abstract »    Full Text »    PDF »
Comparisons of Brain, Uterus, and Liver mRNA Expression for Cytochrome P450s, DNA Methyltransferase-1, and Catechol-O-Methyltransferase in Prepubertal Female Sprague-Dawley Rats Exposed to a Mixture of Aryl Hydrocarbon Receptor Agonists.
D. Desaulniers, G.-H. Xiao, K. Leingartner, I. Chu, B. Musicki, and B. K. Tsang (2005)
Toxicol. Sci. 86, 175-184
   Abstract »    Full Text »    PDF »
Recruitment of DNA methyltransferase I to DNA repair sites.
O. Mortusewicz, L. Schermelleh, J. Walter, M. C. Cardoso, and H. Leonhardt (2005)
PNAS 102, 8905-8909
   Abstract »    Full Text »    PDF »
Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies.
K. N. Bhalla (2005)
J. Clin. Oncol. 23, 3971-3993
   Abstract »    Full Text »    PDF »
MSRE-PCR for analysis of gene-specific DNA methylation.
A. A. Melnikov, R. B. Gartenhaus, A. S. Levenson, N. A. Motchoulskaia, and V. V. Levenson (Chernokhvostov) (2005)
Nucleic Acids Res. 33, e93
   Abstract »    Full Text »    PDF »
Diagnostic and Therapeutic Applications of Epigenetics.
K. Miyamoto and T. Ushijima (2005)
Jpn. J. Clin. Oncol. 35, 293-301
   Abstract »    Full Text »    PDF »
Inactivation of Dnmt3b in Mouse Embryonic Fibroblasts Results in DNA Hypomethylation, Chromosomal Instability, and Spontaneous Immortalization.
J. E. Dodge, M. Okano, F. Dick, N. Tsujimoto, T. Chen, S. Wang, Y. Ueda, N. Dyson, and E. Li (2005)
J. Biol. Chem. 280, 17986-17991
   Abstract »    Full Text »    PDF »
Cancer epigenetics.
P. W. Laird (2005)
Hum. Mol. Genet. 14, R65-R76
   Abstract »    Full Text »    PDF »
Discovery of Aberrant Expression of R-RAS by Cancer-Linked DNA Hypomethylation in Gastric Cancer Using Microarrays.
M. Nishigaki, K. Aoyagi, I. Danjoh, M. Fukaya, K. Yanagihara, H. Sakamoto, T. Yoshida, and H. Sasaki (2005)
Cancer Res. 65, 2115-2124
   Abstract »    Full Text »    PDF »
Chromosomal Instability in Oral Cancer Cells.
S.C. Reshmi and S.M. Gollin (2005)
Journal of Dental Research 84, 107-117
   Abstract »    Full Text »    PDF »
Epigenetic Changes in Prostate Cancer: Implication for Diagnosis and Treatment.
L.-C. Li, P. R. Carroll, and R. Dahiya (2005)
J Natl Cancer Inst 97, 103-115
   Abstract »    Full Text »    PDF »
Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer.
J. Frigola, X. Sole, M. F. Paz, V. Moreno, M. Esteller, G. Capella, and M. A. Peinado (2005)
Hum. Mol. Genet. 14, 319-326
   Abstract »    Full Text »    PDF »
A Genetic Approach to Cancer Epigenetics.
A.P. FEINBERG (2005)
Cold Spring Harb Symp Quant Biol 70, 335-341
   Abstract »    PDF »
Nutrition and Aberrant DNA Methylation Patterns in Atherosclerosis: More than Just Hyperhomocysteinemia?.
S. Zaina, M. W. Lindholm, and G. Lund (2005)
J. Nutr. 135, 5-8
   Abstract »    Full Text »    PDF »
DNA Methylation and Cancer.
P. M. Das and R. Singal (2004)
J. Clin. Oncol. 22, 4632-4642
   Abstract »    Full Text »    PDF »


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