title: Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice.
abstract: Mutator phenotypes, a common and largely unexplained attribute of human cancer, might be better understood in mouse tumors containing reporter genes for accurate mutation enumeration and analysis. Previous work on peritoneal plasmacytomas (PCTs) in mice suggested that PCTs have a mutator phenotype caused by Myc-deregulating chromosomal translocations and/or phagocyte-induced mutagenesis due to chronic inflammation. To investigate this hypothesis, we generated PCTs that harbored the transgenic shuttle vector, pUR288, with a lacZ reporter gene for the assessment of mutations in vivo. PCTs exhibited a 5.5 times higher mutant frequency in lacZ (40.3 +/- 5.1 x 10(-5)) than in normal B cells (7.36 +/- 0.77 x 10(-5)), demonstrating that the tumors exhibit the phenotype of increased mutability. Studies on lacZ mutant frequency in serially transplanted PCTs and phagocyte-induced lacZ mutations in B cells in vitro indicated that mutant levels in tumors are not determined by exogenous damage inflicted by inflammatory cells. In vitro studies with a newly developed transgenic model of inducible Myc expression (Tet-off/MYC) showed that deregulated Myc sensitizes B cells to chemically induced mutations, but does not cause, on its own, mutations in lacZ. These findings suggested that the hypermutability of PCT is governed mainly by intrinsic features of tumor cells, not by deregulated Myc or chronic inflammation.
authors.affiliation: Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Felix
authors.forename: Axel
authors.initials: A
authors.lastname: Polack
authors.forename: Walter
authors.initials: W
authors.lastname: Pretsch
authors.forename: Sharon H
authors.initials: SH
authors.lastname: Jackson
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Georg-Wilhelm
authors.initials: GW
authors.lastname: Bornkamm
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D017930:Genes, Reporter; D016259:Genes, myc / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005822:Genetic Vectors; D007249:Inflammation / Q000150:complications*; D007700:Kinetics; D051379:Mice; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000235:genetics*; D010954:Plasmacytoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D001616:beta-Galactosidase / Q000235:genetics*
chemical_list: D001616:beta-Galactosidase