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

Nagy, Eszter (2014). Characterisation of oncogenic LMP1 and CD40 signals in primary germinal centre B cells and their relevance to the pathogenesis Of Hodgkin’s lymphoma. University of Birmingham. Ph.D.

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Abstract

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.
In 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.
In 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.
In 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.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):