Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alleles
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Animals
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Birth Weight
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Cell Transformation, Neoplastic
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Chromosome Aberrations*
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Chromosomes, Mammalian / genetics*
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Chromosomes, Mammalian / physiology
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation*
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Endogenous Retroviruses / genetics
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Endogenous Retroviruses / physiology
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Gene Expression
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Gene Expression Regulation, Neoplastic
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Gene Rearrangement
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Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
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Genes, myc
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Heterozygote
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Loss of Heterozygosity
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Lymphoma, T-Cell / genetics*
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Lymphoma, T-Cell / pathology
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Mice
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Mice, Transgenic
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Moloney murine leukemia virus / genetics
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Moloney murine leukemia virus / physiology
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Trisomy
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Virus Activation
Substances
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DNA (Cytosine-5-)-Methyltransferase 1
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DNA (Cytosine-5-)-Methyltransferases
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DNMT1 protein, human
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Dnmt1 protein, mouse