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Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals

Oncogene volume 18, pages 39–46 (1999)Cite this article

Abstract

JCV is a papovavirus which is widespread in the human population. The prototype Mad-1 variant of JCV induces a fatal demyelinating disease of the central nervous system (CNS) called Progressive Multifocal Leukoencephalopathy (PML) in immunosuppressed individuals. The unique tropism of JCV (Mad-1) to the CNS is attributed to the tissue-specific regulation of the viral early promoter which is responsible for the production of the viral regulatory protein, T-antigen. The archetype form of this virus, JCV(CY), which has been repeatedly isolated from the urine of PML and non-PML individuals, is distinct from JCV(Mad-1) in the structural organization of the regulatory sequence. To characterize the tissue specific expression of JCV(CY) and to investigate its potential in inducing disease, transgenic mice containing the early region of JCV(CY) were generated. Some of these mice between 9 – 13 months of age exhibited signs of illness as manifested by paralysis of rear limbs, hunched posture, and poor grooming. Neuropathological examination indicated no sign of hypomyelination of the brain, but surprisingly, revealed the presence of primitive tumors originating from the cerebellum and the surrounding brain stem. The tumor masses also infiltrated the surrounding tissue. Results from RNA and protein studies revealed a high level of T-antigen mRNA expression in hindbrains of clinically normal and affected transgenic mice. However, higher levels of T-antigen RNA and protein were detected in brains of the animals exhibiting severe illness. The close resemblance of JCV(CY) induced tumor in transgenic mice to the human medulloblastoma/primitive neuroectodermal tumor (PNETs) in location, histologic appearance, and expression of marker proteins strongly suggests the utility of this novel animal model for the study of human brain tumors.

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Acknowledgements

The authors wish to thank Drs Frisque and Yogo for kindly providing the JCV(CY) construct. We would like to thank past and present members of the Center for NeuroVirology and NeuroOncology for sharing of reagents, ideas, and their insightful discussion, Carlos Lorenzana for technical support in histopathological processing, and Cynthia Schriver for editorial assistance. This work was made possible by a grant awarded by NIH to KK.

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Author notes

  1. Barbara Krynska and Jessica Otte: This work represents equal contribution of B Krynska and J Otte

Authors and Affiliations

  1. Center for NeuroVirology and NeuroOncology, Allegheny University of the Health Sciences, Broad and Vine, MS #406, Philadelphia, 19102, Pennsylvania, USA

    Barbara Krynska, Jessica Otte, Kamel Khalili & Sidney Croul

  2. Department of Genetics, College of Medicine, University of Illinois, 808 Southwood Street, Chicago, 60612, Illinois, USA

    Roberta Franks

  3. Department of Pathology and Laboratory Medicine, Allegheny University of the Health Sciences, Broad and Vine, Philadelphia, 19102, Pennsylvania, USA

    Kamel Khalili & Sidney Croul

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  1. Barbara Krynska
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Krynska, B., Otte, J., Franks, R. et al. Human ubiquitous JCV(CY) T-antigen gene induces brain tumors in experimental animals. Oncogene 18, 39–46 (1999). https://doi.org/10.1038/sj.onc.1202278

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