Analysis of the genome and viral transcriptome of Epstein-Barr virus associated paediatric B cell lymphomas

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Ramagiri, Pradeep (2017). Analysis of the genome and viral transcriptome of Epstein-Barr virus associated paediatric B cell lymphomas. University of Birmingham. Ph.D.

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Abstract

Paediatric Hodgkin lymphoma (HL) and endemic Burkitt lymphoma (eBL) are Epstein-Barr virus (EBV) associated childhood malignancies.

In HL, malignant Hodgkin/Reed-Sternberg (HRS) cells, are characterised by aneuploidy, and comprise <1% of tumour which is challenging for global genetic studies. In chapter 3, I describe the mutational landscape of paediatric HL using in vitro and in silico methods I established, including tumour DNA amplification from low numbers of (~150) microdissected cells. I found that protein-altering mutations converge on mitotic spindle functions and that EBV contributes to transcriptionally downregulate mitotic spindle genes.

The contribution of the EBV to eBL pathogenesis remains poorly understood. In chapter 4, I show that the virus G protein-coupled receptor, BILF1 is apparently a latent gene expressed by tumour cells in a subset of BL. BILF1expression induced a transcriptional profile in primary human germinal centre (GC) B cells that partially recapitulates the transcriptional programme of EBV-positive eBL, and genes up-regulated by BILF1 have functions in oxidative phosphorylation and are also targets for MYC.

In summary, my data identify novel pathogenic pathways contributing to the pathogenesis of two common paediatric B cell malignancies that are likely to have clinical, including therapeutic, relevance.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):