Characterisation of oncogenic LMP1 and CD40 signals in primary germinal centre B cells and their relevance to the pathogenesis Of Hodgkin’s lymphoma

摘要

Latent membrane protein 1 (LMP1) is an oncogene expressed in a subset of germinal centre (GC)-derived lymphomas including Hodgkin’s lymphoma (HL) and diffuse large B cell lymphoma (DLBCL). However, LMP1 shares functional homology with CD40, a receptor required for normal GC B cell development. Dissecting how LMP1 functions differently from CD40 in GC cells is central to a better understanding of lymphomagenesis and is the subject of this thesis. udIn Chapter 3, I show that GC B cells can be successfully isolated from normal human tonsils and that these cells retain a GC phenotype upon short-term culture. udIn Chapter 4 I explore how the transcriptional programmes of LMP1 and CD40 differ in GC B cells and identify a subgroup of genes regulated by LMP1 but not by CD40, which are also concordantly regulated in primary HL cells from which I focus on sphingosine-1-phosphate receptor 2 (S1PR2). I confirm that S1PR2 is an LMP1 target in GC B cells and show that it is not expressed in the tumour cells of the majority of cases of HL and DLBCL. In DLBCL, S1PR2 loss is associated with LMP1 expression. I also provide preliminary evidence that the over-expression of S1PR2 can inhibit the HL cell migration.udIn Chapter 5, I report my initial attempts to optimise a method for the measurement of the activity of transcription factors in GC B cells which can be used to delineate those pathways activated by LMP1, but not by CD40, in GC B cells.ud