This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Felix, K. Articles by Janz, S. Search for Related Content PubMed PubMed Citation Articles by Felix, K. Articles by Janz, S.

Moderate Hypermutability of a Transgenic lacZ Reporter Gene in Myc-Dependent Inflammation-Induced Plasma Cell Tumors in Mice

¹ Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, and
⁴ Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland;
² Institute of Molecular Biology and Tumor Genetics, Munich, Germany;
³ Institute of Mammalian Genetics, Neuherberg, Germany; and
⁵ Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, Maryland

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.

This article has been cited by other articles:

				S. Ray, K. R. Atkuri, D. Deb-Basu, A. S. Adler, H. Y. Chang, L. A. Herzenberg, and D. W. Felsher MYC Can Induce DNA Breaks In vivo and In vitro Independent of Reactive Oxygen Species. Cancer Res., July 1, 2006; 66(13): 6598 - 6605. [Abstract] [Full Text] [PDF]

				J. R. Stringer, J. S. Larson, J. M. Fischer, M. Medvedovic, M. N. Hersh, G. P. Boivin, and S. L. Stringer Modeling variation in tumors in vivo PNAS, February 15, 2005; 102(7): 2408 - 2413. [Abstract] [Full Text] [PDF]