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Title: Investigating N-glycosylation sites in follicular lymphoma surface immunoglobulin and their role in lymphoma initiation
Author: Odabashian, Mariette
ISNI:       0000 0004 7966 6349
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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Follicular lymphoma (FL) is an incurable indolent non-Hodgkin's lymphoma that is both biologically and clinically heterogeneous. Despite the loss of one immunoglobulin allele through the t14;18 translocation and ongoing somatic hypermutation (SHM) of the immunoglobulin heavy chain variable region genes (IGHV), all detectable tumour subclones retain functional expression of the surface immunoglobulin throughout disease, resulting in thousands of tumour subclones displaying distinct but clonally related IGHV sequences. This retention suggests a tumour dependence on signalling through the B cell receptor (BCR). >90% of FL cases contain N-glycosylation (N-gly) motifs in their IGHV which are acquired through SHM. Motifs are rarely found in normal somatically mutated B cells, indicative of a pathogenic function. Mannoses attach to motifs and activate BCR signalling pathways following engagement with lectins DC-SIGN and MR, expressed by microenvironmental immune cells. This novel interaction could represent a critical mechanism by which tumour cells survive in the hostile microenvironment. Utilising a next-generation sequencing approach, we determined using temporal tumour samples from a diverse group of patients the behaviour of N-gly motifs during tumour evolution and progression to elucidate their importance in lymphomagenesis. Remarkably, we observed conservation of N-gly motif sites in >97% of subclone populations within and across disease events of all patients, inferring motifs are an early and stable event of pathogenesis. Rare motif negative subclones were presumably lost or negligible from successive events in contrast to motif positive subclones that were able to migrate between anatomical sites. This positive selection suggests an ongoing reliance of N-gly sites during disease progression, despite the changing genomic landscape of tumour clones. Interrogation of the microenvironmental landscape through novel, multiplex phenotyping analysis provided new insight into DC-SIGN and MR expression on immune cells of healthy and FL derived lymph nodes. A greater population of follicular dendritic cells, macrophages and M2 macrophages within tumour lymph nodes expressed a MR+ and DCSIGN+MR+ phenotype, indicating a remodelling of the microenvironment in disease that could be contributed by the mannose- lectin interaction. Targeting motifs or the inferred mannose-lectin interaction may lead to therapeutic benefit.
Supervisor: Not available Sponsor: Pathological Society of Great Britain and Ireland
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available