Phenotype and frequency of Epstein-Barr virus-infected cells in pretreatment blood samples from patients with Hodgkin lymphoma.

An accumulating body of data suggests that the Epstein-Barr virus (EBV), a lymphotropic herpesvirus, is involved in the pathogenesis of a proportion of cases of Hodgkin lymphoma (HL). In this study, we showed that the frequency of circulating EBV-infected cells was significantly higher (P < 0.001) in pretreatment blood samples from EBV-associated cases when compared with non-EBV-associated cases. We further showed that in patients with EBV-associated disease, the virus persisted in the peripheral blood in memory B cells. This phenotype is consistent with that seen in healthy seropositive controls, post-transplant patients and patients with acute infectious mononucleosis. The data suggest that an increased frequency of EBV carrying B cells in peripheral blood is associated with EBV-associated HL.

Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection.

The development of T cells in the thymus is regulated by a series of stage-specific transcription factors. Deregulated expression of these factors can lead to alterations in thymocyte development with the production of aberrant cell subsets and predispose to tumor formation. The three genes of the Runx family are multilineage regulators of differentiation that have been reported to be expressed in the T cell lineage. However, their roles in thymocyte development and T cell function are largely unknown. While the Runx2/Cbfa1/AML3/Pebp2alphaa gene plays a primary role in osteogenesis and regulates a number of key bone regulatory genes, we show here that Runx2 is also expressed during the earliest phase of thymic development, in the double-negative subset. Furthermore, enforced expression of Runx2 in transgenic mice under the CD2 promoter was found to affect T cell development at a stage coincident with beta-selection, resulting in an expansion of double-negative CD4 and CD8 immature single-positive cells. Unlike wild-type controls this preselection population (CD4-CD8+heat-stable Ag+TCR-) is in a nonproliferative state, but appears to be primed for further transformation events. Overall the data suggest that Runx2 accelerates development to the CD8 immature single-positive stage, but retards subsequent differentiation to the double-positive stage. Thus, Runx2 joins a small group of transcription factors that can interfere with early T cell development, cause an expansion of a specific subset, and predispose to lymphoma.

Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins.

The papillomavirus E5 protein is localized in the endoplasmic reticulum (ER) and Golgi apparatus (GA) of the host cell. Transformed bovine fibroblasts expressing bovine papillomavirus (BPV) E5 are highly vacuolated and have a much enlarged, distorted and fragmented GA. Major histocompatibility complex class I (MHC I) is processed and transported to the cell surface through the GA. Given the cellular localization of E5 in the GA and the morphologically abnormal GA, we investigated the expression of MHC I in cells transformed by E5 from BPV-1 and BPV-4. Two cell lines were used: bovine cells that also express E6, E7 and activated ras, and NIH3T3 cells that express only E5. In addition, PalF cells acutely infected with a recombinant retrovirus expressing E5 were also examined. In contrast to non-transformed normal cells, or transformed cells expressing other papillomavirus proteins, cells expressing E5 do not express MHC I on their surface, but retain it intracellularly, independently of the presence of other viral or cellular oncogenes, or of whether the cells are long-term transformants or acutely infected. We conclude that expression of E5 prevents expression of MHC I to the cell surface and causes its retention within the cell. In addition, lower amounts of total MHC I heavy chain and of heavy chain RNA are detected in E5-transformed cells than in control cells. As surface expression of another glycosylated membrane protein, the transferrin receptor, is not affected, it appears that E5 targets MHC I with at least a degree of specificity. In papillomavirus lesions this effect would have important implications for antigen presentation by, and immunosurveillance of, virally infected cells.