DNA amplification in glial cells of progressive multifocal leukoencephalopathy: an image analysis study

Department of Pathology, Hospital Germans Trias i Pujol, Barcelona, Spain.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 3.8). 07/1996; 55(6):729-33. DOI: 10.1097/00005072-199606000-00007
Source: PubMed


JC virus (JCV), the agent of progressive multifocal leukoencephalopathy (PML), has been shown by both immunohistochemistry and flow cytometry to be associated with p53 protein stabilization. Since stabilization/inactivation of p53 is associated with the development of genomic instability, abnormal cell DNA contents are to be expected in JCV-infected cells of PML. This work explores that possibility by image analysis evaluation of DNA content in PML-infected oligodendrocytes and bizarre astrocytes. Brain paraffin sections of PML lesions from five adult male patients with the acquired immune deficiency syndrome (AIDS) were treated with the Feulgen technique to obtain a stochiometric staining of DNA and analyzed with a microscope image processor. Inclusion-bearing oligodendrocytes exhibited near tetraploid DNA indices in each of the five cases, whereas atypical astrocytes were in the hypertetraploid range in all cases and were polyploid in four instances. This evidence of DNA amplification in PML glial cells is congruent with the functional abolition of p53 protein in association with JCV infection and lends further support to the role of p53 as a keeper of diploid status and guardian of genomic stability.

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    • "Antibody titres to JCV have been correlated to chromosomal aberrations occurring in lymphocytes (Lazutka et al., 1996; Neel et al., 1996) and JCV infection of human colonic cells induces chromosomal instability and changes in ploidy (Ricciardiello et al., 2003). In the case of PML, stoichiometric analysis of cellular DNA content using the Feulgen technique indicated the occurrence of hyperploidy in inclusion-bearing oligodendrocytes and bizarre astrocytes (Ariza et al, 1996). There is evidence that the closely related polyomaviruses BKV and SV40 also induce genomic instability (reviewed by White et al., 2005). "
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    ABSTRACT: Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the CNS caused by infection of glial cells with the polyomavirus, JCV. Here we report that genomic stability and DNA repair are significantly dysregulated by JCV infection of human astrocytes. Metaphase spreads exhibited increased ploidy correlating with duration of infection. Increased micronuclei formation and phospho-Histone2AX expression also indicated DNA damage. Western blot analysis revealed perturbation in expression of some DNA repair proteins including a large elevation of Rad51. Immunohistochemistry on clinical samples of PML showed robust labeling for Rad51 in nuclei of bizarre astrocytes and inclusion body-bearing oligodendrocytes that are characteristic of JCV infection. Finally, in vitro end-joining DNA repair was altered in extracts prepared from JCV-infected human astrocytes. Alterations in DNA repair pathways may be important for the life cycle of JCV and the pathogenesis of PML.
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    ABSTRACT: The human JC virus (JCV) is a neurotropic polyomavirus that is the etiologic agent of progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system occurring mainly in patients with advanced HIV infection. JCV is also associated with tumors of the brain and other organs as evidenced from the analysis of clinical samples for the presence of JCV DNA sequences and the expression of viral proteins. In addition, JCV is highly oncogenic in experimental animals and transforms cells in culture. JCV encodes three non-capsid regulatory proteins: large T-antigen,
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