Pathogenesis of Germinal Centre Derived B Cell Lymphomas
Many of the commonest human lymphomas (including follicular, diffuse large B cell and Burkitt lymphomas) develop from a specific stage of B lymphocyte differentiation termed the Germinal Centre. Normal B lymphocytes form part of our adaptive immune system. B cells encountering a foreign antigen in the context of T cell help initiate the formation of transient microanatomical structures termed germinal centres. Within germinal centres B cells undergo multiple rounds of intense proliferation coupled with somatic hypermutation of the immunoglobulin genes that alter the affinity for antigen. Those with greater affinity for antigen successfully compete for T cell help before exiting the germinal centre as immunoglobulin secreting plasma cells or memory B cells, whereas less competitive B cells default to apoptosis. Rapidly changing, but tightly controlled, programmes of gene expression determine successive cell fate choices during the germinal centre reaction. It is the loss of this tight control and the resulting corruption of cell fate choices within the germinal centre that results in the development of malignant lymphoma and that forms the focus of my group’s research.
The networks of transcription factors that regulate the germinal centre reaction have been well characterised in recent years. Their importance is underscored by the finding of recurrent somatic mutation in these transcriptional regulators in next generation sequencing studies of GC derived lymphomas. It has recently become clear that a major tier of regulation is also imposed in a highly dynamic fashion at the level of translation. Importantly, translation control is invisible to conventional gene expression profiling techniques such as microarray or RNA-seq and so the contribution of translational regulation to the control of either normal or malignant gene expression remains poorly studied. A particular focus of our group is the use of transcriptome wide translational profiling to understand how normal gene expression becomes corrupted at the level of translation during the development of lymphoma. Furthermore, we wish to reveal how this corruption of translation is brought about by somatic mutation of RNA-binding proteins that control translation (translation factors) and by the activation of oncogenic signalling pathways that regulate the activity of these translation factors. Finally we wish to characterise how new therapeutic agents that are entering trials for lymphoma may exert some of their effect though changes in translation and conversely how resistance to these agents may arise by feedback mechanisms acting at the level of mRNA translation.
Keywords: B-cell, Germinal Centre, Lymphoma, Translation, RNA-binding protein
Clinical conditions: Diffuse Large B Cell Lymphoma, Burkitt Lymphoma, Follicular Lymphoma
Methodologies: RNA-Seq, Ribosome Profiling, iCLIP, Primary human lymphocyte culture and transduction
Martin Turner, Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge
Brian Huntly, Department of Haematology, Cambridge
George Vassiliou, Department of Haematology, Cambridge
Shamith Samarajiwa, Integrative Systems Biomedicine Group, MRC Cancer Unit, Cambridge
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