International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


wednesday 20 november

08:30 09:00 hrs


N Copeland
National Cancer Institute

Co-Authors: 1) Suzuki T, 1) Liu P, 1) Warming S, 1) Hisa T, 1) Spence S, 1) Fujita M, 1) Tessarollo L, 1) Shen H, 1) Akagi K, 2) Morse III H, 1) Ward J, 3) Malley J, 4) Naiman D, 5) Nakamura T, 6) Ortiz M, 6) Keller J, 1) Jenkins N
Institutions: 1) National Cancer Institute, 2) National Institute of Allergy and Infectious Diseases, 3) National Institutes of Health, 4) Johns Hopkins University, 5) Japanese Foundation for Cancer Research, 6) SAIC-Frederick

Retroviral insertional mutagenesis in inbred mouse strains with a high spontaneous incidence of retrovirally induced hematopoietic disease provides a potent cancer gene discovery tool. To demonstrate the power of retroviral insertional mutagenesis for cancer gene discovery in the post-genome-sequence era, we used a high throughput inverse PCR method to clone and sequence 1336 retroviral integration sites from murine hematopoietic tumors, and then mapped 1199 of these sequences on the mouse genome using the Celera and/or public mouse sequence databases. These studies identified 153 loci that are targets of viral integration in more than one tumor and therefore likely to encode a disease gene. Twenty-eight of these loci encode genes that are known or suspected human cancer genes, while another nine encode homologs of human cancer genes. Many other loci encode excellent disease gene candidates but a role for these genes in human disease has yet to be evaluated. Several of these genes function in pathways already associated with hematopoietic disease, while others other are likely to identify new hematopoietic disease pathways. In a number of cases, more than one disease gene was identified in the same tumor, providing genetic evidence for cooperativity between genes. Finally, we and others, have shown that several of these genes function as key regulators of hematopoietic cell growth and differentiation; therefore proviral tagging also provides a means for identifying new regulators of hematopoiesis

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