Induction of Tumors in Mice by Genomic Hypomethylation

Author:

Gaudet François1234,Hodgson J. Graeme1234,Eden Amir1234,Jackson-Grusby Laurie1234,Dausman Jessica1234,Gray Joe W.1234,Leonhardt Heinrich1234,Jaenisch Rudolf1234

Affiliation:

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.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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