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Molecular and Cellular Biology, September 2006, p. 6713-6726, Vol. 26, No. 17
0270-7306/06/$08.00+0     doi:10.1128/MCB.00296-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Mutation of the Murine Bloom's Syndrome Gene Produces Global Genome Destabilization

Nicholas Chester,^* Holger Babbe, Jan Pinkas, Charlene Manning, and Philip Leder

Department of Genetics, Harvard Medical School, 356 New Research Building, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115

Received 16 February 2006/ Returned for modification 16 March 2006/ Accepted 15 June 2006

Bloom's syndrome (BS) is a genetic disorder characterized cellularly by increases in sister chromatid exchanges (SCEs) and numbers of micronuclei. BS is caused by mutation in the BLM DNA helicase gene and involves a greatly enhanced risk of developing the range of malignancies seen in the general population. With a mouse model for the disease, we set out to determine the relationship between genomic instability and neoplasia. We used a novel two-step analysis to investigate a panel of eight cell lines developed from mammary tumors that appeared in Blm conditional knockout mice. First, the panel of cell lines was examined for instability. High numbers of SCEs were uniformly seen in members of the panel, and several lines produced chromosomal instability (CIN) manifested by high numbers of chromosomal structural aberrations (CAs) and chromosome missegregation events. Second, to see if Blm mutation was responsible for the CIN, time-dependent analysis was conducted on a tumor line harboring a functional floxed Blm allele. The floxed allele was deleted in vitro, and mutant as well as control subclones were cultured for 100 passages. By passage 100, six of nine mutant subclones had acquired high CIN. Nine mutant subclones produced 50-fold more CAs than did nine control subclones. Finally, chromosome loss preceded the appearance of CIN, suggesting that this loss provides a potential mechanism for the induction of instability in mutant subclones. Such aneuploidy or CIN is a universal feature of neoplasia but has an uncertain function in oncogenesis. Our results show that Blm gene mutation produces this instability, strengthening a role for CIN in the development of human cancer.

Present address: Amgen, One Kendall Square, Cambridge, MA 02139.

Present address: Genzyme Corporation, 5 Mountain Road, Framingham, MA 01701.

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