dc.contributor.author | Odabashian, M | en_US |
dc.contributor.author | Carlotti, E | en_US |
dc.contributor.author | Araf, S | en_US |
dc.contributor.author | Okosun, J | en_US |
dc.contributor.author | Spada, F | en_US |
dc.contributor.author | Gribben, JG | en_US |
dc.contributor.author | Forconi, F | en_US |
dc.contributor.author | Stevenson, FK | en_US |
dc.contributor.author | Calaminici, M | en_US |
dc.contributor.author | Krysov, S | en_US |
dc.date.accessioned | 2020-03-27T16:25:51Z | |
dc.date.available | 2019-12-13 | en_US |
dc.date.issued | 2020-03-12 | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/63344 | |
dc.description.abstract | Follicular 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.extent | 834 - 844 | en_US |
dc.language | eng | en_US |
dc.language.iso | en | en_US |
dc.relation.ispartof | Blood | en_US |
dc.title | IGHV sequencing reveals acquired N-glycosylation sites as a clonal and stable event during follicular lymphoma evolution. | en_US |
dc.type | Article | |
dc.rights.holder | This 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.doi | 10.1182/blood.2019002279 | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/31932843 | en_US |
pubs.issue | 11 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 135 | en_US |
dcterms.dateAccepted | 2019-12-13 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | Composition of the peripheral blood of CLL patients; interactions and activation of B and T cells::Barts Cancer Charity | en_US |
qmul.funder | Composition of the peripheral blood of CLL patients; interactions and activation of B and T cells::Barts Cancer Charity | en_US |