The latency-associated nuclear antigen of Kaposi sarcoma–associated herpesvirus induces B cell hyperplasia and lymphoma
Farnaz D. Fakhari, Joseph H. Jeong, Yogita Kanan, Dirk P. Dittmer
Farnaz D. Fakhari, Joseph H. Jeong, Yogita Kanan, Dirk P. Dittmer
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Research Article Immunology

The latency-associated nuclear antigen of Kaposi sarcoma–associated herpesvirus induces B cell hyperplasia and lymphoma

Abstract

Kaposi sarcoma–associated herpesvirus (KSHV) is a human lymphotropic herpesvirus. It is implicated in B cell neoplasias such as primary effusion lymphoma and multicentric Castleman disease in AIDS patients. The KSHV latency-associated nuclear antigen (LANA) is consistently expressed in all KSHV-associated tumor cells and was shown to bind the tumor suppressor proteins p53 and pRb. To test LANA’s contribution to lymphomagenesis in vivo we generated transgenic mice expressing LANA under the control of its own promoter, which is B cell specific. All of the transgenic mice developed splenic follicular hyperplasia due to an expansion of IgM+IgD+ B cells and showed increased germinal center formation. We also observed lymphomas, implying that LANA can activate B cells and provide the first step toward lymphomagenesis.

Authors

Farnaz D. Fakhari, Joseph H. Jeong, Yogita Kanan, Dirk P. Dittmer

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Figure 1

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Development of LANA transgenic mice. (A) The LANA transcription locus (1...
Development of LANA transgenic mice. (A) The LANA transcription locus (14) and transgene construct carrying LacZneo (27) as previously described and the LANA transgene construct used here. SV40 pA, simian virus 40 poly A; β-geo, β-galactosidase-neomycin; TK, thymidine kinase. (B) Southern blot analysis of tail DNA, digested with BamHI and hybridized with a LANA-specific probe to reveal the founder-specific integration sites. Lane 1 shows the transgene plasmid as a positive control (Pos.), lane 5 contains the DNA from a C57BL/6 mouse as negative control (Neg.), and remaining lanes represent DNA from LANA transgenic animals belonging to lines i, ii, and iii (animals 4 and 6 are siblings). Arrowhead indicates a fragment specific for all transgenic animals; other bands are integration-site specific. (C and D) Real-time quantitative RT-PCR analysis of spleen samples for LANA transgene mRNA or apoB housekeeping mRNA resolved on a 2% tris-borate-EDTA–agarose gel and (C) subsequent Southern blot analysis with a probe specific for LANA (LANA-P). Lanes i–v refer to spleen RNA from 5 different transgene-positive animals. NTC, nontemplate control; MW, 100-bp molecular weight marker. (D) Lanes 1–3 show transgene-negative, and lanes 4–6 transgene-positive, littermates after backcross into the C57BL/6 background.