Classical Hodgkin's disease (HD) is the most common lymphoma in the Western World. The malignant cells in HD are the so-called Hodgkin and Reed-Sternberg (HRS) cells, which comprise only a few percent or less of the lymphoma tissue. In roughly half of the patients, the HRS cells are infected with Epstein-Barr-Virus (EBV) and express the EBV-encoded membrane proteins LMP1 and LMP2A. These proteins are constitutively active and in B cells partially mimic signals of the CD40 co-receptor and the antigen receptor (BCR), respectively. Based on these circumstances and on our own molecular analysis of Ig gene rearrangements in micro manipulated HRS cells we have developed a scenario of HD pathogenesis. In this scenario, HRS cells derive in most instances from pre-apoptotic germinal center (GC) B cells rescued by some transforming event(s). In EBV+ HD, LMP1 and LMP2A may participate in this initial rescue.
The aim of this proposal is to reconstruct this scenario in the mouse by conditional gene targeting techniques. We have developed a mouse mutant in which Cre recombinase is efficiently expressed in GC but not naive B cells. This will be used to target expression of LMP2A and/or LMP1 to GC B cells in vivo. The interference of the viral proteins with the GC reaction will be investigated. Rescue of pre-apoptotic GC B cells that have lost BCR expression because of somatic hypermutation might be observed, as well as lymphomagenesis, given the known oncogenic properties of LMP1. These experiments will be complemented by an attempt to target another potential tumor determinant of HRS cells into GC B cells, namely the activated form of Notch1. This molecule has recently been shown to be expressed in HRS cells at high levels and in an activated form. Notch1 is particularly attractive in this context, because it is involved in lineage decisions in lymphocyte progenitors, promoting T cell development. Curiously, HRS cells have down regulated many B cell-specific genes and express molecular markers of other hematopoietic lineages, including T cells. Notch1, which is also a potent oncogene if ectopically expressed, might thus contribute to this curious phenotype as well as to HRS cell transformation. Combining LMP2A, LMP1 and Notch1 expression in GC B cells by conditional gene targeting might lead to a mouse model of HD. Apart from lymphomagenesis, the proposed experiments should also lead to new insights into the biology of the GC reaction in the context of EBV infection.
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