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dc.contributor.authorOdabashian, Men_US
dc.contributor.authorCarlotti, Een_US
dc.contributor.authorAraf, Sen_US
dc.contributor.authorOkosun, Jen_US
dc.contributor.authorSpada, Fen_US
dc.contributor.authorGribben, JGen_US
dc.contributor.authorForconi, Fen_US
dc.contributor.authorStevenson, FKen_US
dc.contributor.authorCalaminici, Men_US
dc.contributor.authorKrysov, Sen_US
dc.date.accessioned2020-03-27T16:25:51Z
dc.date.available2019-12-13en_US
dc.date.issued2020-03-12en_US
dc.identifier.urihttps://qmro.qmul.ac.uk/xmlui/handle/123456789/63344
dc.description.abstractFollicular lymphoma B cells undergo continuous somatic hypermutation (SHM) of their immunoglobulin variable region genes, generating a heterogeneous tumor population. SHM introduces DNA sequences encoding N-glycosylation sites asparagine-X-serine/threonine (N-gly sites) within the V-region that are rarely found in normal B-cell counterparts. Unique attached oligomannoses activate B-cell receptor signaling pathways after engagement with calcium-dependent lectins expressed by tissue macrophages. This novel interaction appears critical for tumor growth and survival. To elucidate the significance of N-gly site presence and loss during ongoing SHM, we tracked site behavior during tumor evolution and progression in a diverse group of patients through next-generation sequencing. A hierarchy of subclones was visualized through lineage trees based on SHM semblance between subclones and their discordance from the germline sequence. We observed conservation of N-gly sites in more than 96% of subclone populations within and across diagnostic, progression, and transformation events. Rare N-gly-negative subclones were lost or negligible from successive events, in contrast to N-gly-positive subclones, which could additionally migrate between anatomical sites. Ongoing SHM of the N-gly sites resulted in subclones with different amino acid compositions across disease events, yet the vast majority of resulting DNA sequences still encoded for an N-gly site. The selection and expansion of only N-gly-positive subclones is evidence of the tumor cells' dependence on sites, despite the changing genomic complexity as the disease progresses. N-gly sites were gained in the earliest identified lymphoma cells, indicating they are an early and stable event of pathogenesis. Targeting the inferred mannose-lectin interaction holds therapeutic promise.en_US
dc.format.extent834 - 844en_US
dc.languageengen_US
dc.language.isoenen_US
dc.relation.ispartofBlooden_US
dc.titleIGHV sequencing reveals acquired N-glycosylation sites as a clonal and stable event during follicular lymphoma evolution.en_US
dc.typeArticle
dc.rights.holderThis research was originally published in Blood. Mariette Odabashian, Emanuela Carlotti, Shamzah Araf, Jessica Okosun, Filomena Spada, John G. Gribben, Francesco Forconi, Freda K. Stevenson, Mariarita Calaminici, Sergey Krysov; IGHV sequencing reveals acquired N-glycosylation sites as a clonal and stable event during follicular lymphoma evolution. Blood 2020; 135 (11): 834–844. doi: https://doi.org/10.1182/blood.2019002279. © the American Society of Hematology.
dc.identifier.doi10.1182/blood.2019002279en_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/31932843en_US
pubs.issue11en_US
pubs.notesNot knownen_US
pubs.publication-statusPublisheden_US
pubs.volume135en_US
dcterms.dateAccepted2019-12-13en_US
rioxxterms.funderDefault funderen_US
rioxxterms.identifier.projectDefault projecten_US
qmul.funderComposition of the peripheral blood of CLL patients; interactions and activation of B and T cells::Barts Cancer Charityen_US
qmul.funderComposition of the peripheral blood of CLL patients; interactions and activation of B and T cells::Barts Cancer Charityen_US


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