Transgenic mouse model of IgM+lymphoproliferative disease mimicking Waldenström macroglobulinemia.
Waldenström macroglobulinemia (WM) is a low-grade incurable immunoglobulin M+(IgM+) lymphoplasmacytic lymphoma for which a genetically engineered mouse model of de novo tumor development is lacking. On the basis of evidence that the pro-inflammatory cytokine, interleukin 6 (IL6), and the survival-enhancing oncoprotein, B cell leukemia 2 (BCL2), have critical roles in the natural history of WM, we hypothesized that the enforced expression of IL6 and BCL2 in mice unable to perform immunoglobulin class switch recombination may result in a lymphoproliferative disease that mimics WM. To evaluate this possibility, we generated compound transgenic BALB/c mice that harbored the human BCL2 and IL6 transgenes, EμSV-BCL2-22 and H2-Ld-hIL6, on the genetic background of activation-induced cytidine deaminase (AID) deficiency. We designated these mice BCL2+IL6+AID-and found that they developed-with full genetic penetrance (100% incidence) and suitably short latency (93 days median survival)-a severe IgM+lymphoproliferative disorder that recapitulated important features of human WM. However, the BCL2+IL6+AID-model also exhibited shortcomings, such as low serum IgM levels and histopathological changes not seen in patients with WM, collectively indicating that further refinements of the model are required to achieve better correlations with disease characteristics of WM.
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Tompkins
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.|Bioinformatics Division, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Sompallae
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Rosean
Department of Radiology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Walsh
Department of Radiology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Acevedo
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
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Kovalchuk
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Han
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Jing
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Holman
Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
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Rehg
International Waldenstrom's Macroglobulinemia Foundation, Sarasota, FL, USA.
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Herms
Department of Radiology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Sunderland
Virology and Cellular Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
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Morse
Department of Pathology, Iowa Institute of Human Genetics, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
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Janz
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008258:Waldenstrom Macroglobulinemia / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000473:pathology
D007075:Immunoglobulin M