Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice

Klaus FELIX; Axel POLACK; Walter PRETSCH; Sharon H JACKSON; Lionel FEIGENBAUM; Georg-Wilhelm BORNKAMM; Siegfried JANZ

doi:10.1158/0008-5472.CAN-03-2602

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Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice

Journal article

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Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice

Klaus FELIX, Axel POLACK, Walter PRETSCH, Sharon H JACKSON, Lionel FEIGENBAUM, Georg-Wilhelm BORNKAMM and Siegfried JANZ

Cancer research (Chicago, Ill.), Vol.64(2), pp.530-537

2004

DOI: 10.1158/0008-5472.CAN-03-2602

PMID: 14744766

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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.

Antineoplastic Agents

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Biological and medical sciences

Medical sciences

Pharmacology. Drug treatments

Details

Title: Subtitle: Moderate hypermutability of a transgenic lacZ reporter gene in Myc-dependent inflammation-induced plasma cell tumors in mice
Creators: Klaus FELIX - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Axel POLACK - Laboratory of Host Defense, National Institute of Allergy and Infectious diseases, NIH, Bethesda, Maryland, United States
Walter PRETSCH - Institute of Molecular Biology and Tumor Genetics, Munich, Germany
Sharon H JACKSON - Institute of Mammalian Genetics, Neuherberg, Germany
Lionel FEIGENBAUM - Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, Maryland, United States
Georg-Wilhelm BORNKAMM - Laboratory of Host Defense, National Institute of Allergy and Infectious diseases, NIH, Bethesda, Maryland, United States
Siegfried JANZ - Laboratory of Genetics, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, United States
Resource Type: Journal article
Publication Details: Cancer research (Chicago, Ill.), Vol.64(2), pp.530-537
DOI: 10.1158/0008-5472.CAN-03-2602
PMID: 14744766
NLM abbreviation: Cancer Res
ISSN: 0008-5472
eISSN: 1538-7445
Publisher: American Association for Cancer Research
Language: English
Date published: 2004
Academic Unit: Pathology
Record Identifier: 9984083219202771

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