Biology subjects

Arthur, S. E.

Publications and source records attributed to Arthur, S. E..

5 recordsLinked to original sources

bioRxiv2021

Shared and distinct genetic features in human and canine B-cell lymphomas

Animal models of human cancers are an important tool for the development and preclinical evaluation of therapeutics. Canine B-cell lymphoma (cBCL) is an appealing model for human mature B-cell neoplasms due to the high sequence similarity in cancer genes to humans and inactive telomerase in adult tissues. We performed targeted sequencing on 86 canine patients from the Canine Comparative Oncology Genomic Consortium, with 61 confirmed as B-cell lymphomas. We confirmed a high frequency of mutations in TRAF3 (45%) and FBXW7 (20%) as has been reported by our group and others. We also note a higher frequency of DDX3X (20%) and MYC (13%) mutations in our canine cohort. We compared the pattern and incidence of mutations in cBCL to human diffuse large B-cell lymphoma (hDLBCL) and human Burkitt lymphoma (hBL). Canine MYC mutations displayed a focal pattern with 80% of mutations affecting the conserved phosphodegron sequence in MYC box 1, which are known to stabilize MYC protein. We also note that MYC and FBXW7 mutations do not co-occur in our cBCL cohort, leading to the hypothesis that these mutations represent alternative approaches to stabilize MYC in canine lymphoma. We observed striking differences in the pattern of DDX3X mutations in canine lymphoma as compared to hBL and uncovered a sex-specific pattern of DDX3X mutations in hBL that is not consistent with those identified in canine lymphomas. In sum, we describe key differences between cBCL and human mature B-cell lymphomas which may indicate differences in the biology of these cancers. This should be considered in future studies of cBCL as a model of human lymphomas.

cancer biology↗

bioRxiv2021

Leaked genomic and mitochondrial DNA contribute to the host response to noroviruses in a STING-dependent manner

The cGAS-STING pathway is central to the IFN response against DNA viruses. However, recent studies are increasingly demonstrating its role in the restriction of some RNA viruses. Here we show that the cGAS-STING pathway also contributes to the IFN response against noroviruses, positive-sense single-stranded RNA viruses that are now one of the most common causes of infectious gastroenteritis world-wide. We show a significant reduction in IFN-{beta} induction and a corresponding increase in viral replication in norovirus-infected cells following STING inhibition, knockdown or deletion. Upstream of STING, we show that cells lacking either cGAS or IFI16 also have severely impaired IFN responses. Further, we demonstrate that immunostimulatory host genome-derived DNA, and to a lesser extent mitochondrial DNA, accumulate in the cytosol of norovirus-infected cells. And lastly, overexpression of the viral NS4 protein was sufficient to drive the accumulation of cytosolic DNA. Together, our data elucidate a role for cGAS, IFI16 and STING in the restriction of noroviruses, and demonstrate for the first time the utility of host genomic DNA as a damage-associated molecular pattern in cells infected with an RNA virus. HighlightsO_LIcGAS, IFI16 and STING are required for a robust IFN response against noroviruses C_LIO_LINuclear and mitochondrial DNA accumulate in the cytosols of infected cells C_LIO_LIViral NS4 mediates accumulation of cytosolic DNA C_LI

molecular biology↗

bioRxiv2021

Non-coding NFKBIZ 3' UTR mutations promote cell growth and resistance to targeted therapies in diffuse large B-cell lymphoma

Amplifications and non-coding 3' UTR mutations affecting NFKBIZ have been identified as recurrent genetic events in diffuse large B-cell lymphoma (DLBCL). We confirm the prevalence and pattern of NFKBIZ 3' UTR mutations in independent cohorts and determine they are enriched in the ABC subtype as well as the recently described novel BN2/C1/NOTCH2 classes of DLBCL. Presently, the effects of and mechanism by which non-coding mutations can act as cancer drivers has been relatively unexplored. Here, we provide a functional characterization of these non-coding NFKBIZ 3' UTR mutations. We demonstrate that the resulting elevated expression of I{kappa}B-{zeta} confers growth advantage in DLBCL cell lines and primary germinal center B-cells as well as nominate novel I{kappa}B-{zeta} target genes with potential therapeutic implications. The limited responses to targeted treatments in DLBCL, particularly those targeting the NF-{kappa}B axis, led us to investigate and confirm that NFKBIZ 3' UTR mutations affect response to therapeutics and suggest it may be a useful predictive biomarker. Statement of SignificanceThrough functional characterization we reveal that non-coding NFKBIZ 3' UTR mutations are a common driver in DLBCL, and mutation status may be a relevant biomarker to predict poor response to therapeutics targeting the NF-{kappa}B pathway.

cancer biology↗

bioRxiv2019

Coding and regulatory drivers of mantle cell lymphoma identified through exome and genome sequencing

Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) that is incurable with standard therapies. The genetic drivers of this cancer have not been firmly established and the features known to contribute to differences in clinical course remain limited. To extend our understanding of the biological pathways involved in this malignancy, we performed a large-scale genomic analysis of MCL using data from 51 exomes alongside previously published exome cohorts. To confirm our findings, we re-sequenced the genes identified in the exome cohort in 212 MCL tumors, each having clinical follow-up data. We confirmed the prognostic association of TP53 and NOTCH1 mutations and further nominate two additional genes, EWSR1 and MEF2B, whose mutation respectively associated with poor and good outcome. Our sequencing revealed novel recurrent mutations including a unique missense hot spot in MEF2B and a pattern of non-coding mutations surrounding a single exon of the HNRNPH1 gene. We sequenced the whole genomes of 34 MCLs to confirm the focal nature of HNRNPH1 mutations. Using RNA-seq data from 110 of these cases, we identified a functional role for recurrent non-coding HNRNPH1 mutations in disrupting an auto-regulatory feedback mechanism. Overall, we identified three novel MCL-related genes with roles in RNA trafficking or splicing, namely DAZAP1, EWSR1, and HNRNPH1. Taken together, these data strongly implicate a role for aberrant regulation of splicing in MCL pathobiology.\n\nKey pointsO_LIRNA-binding proteins with roles in regulating alternative splicing, DAZAP1, EWSR1, HNRNPH1, are frequently mutated in MCL\nC_LIO_LIThe majority of recurrent somatic HNRNPH1 mutations are intronic and HNRNPH1 exhibits self-regulation through alternative splicing\nC_LI

genomics↗

bioRxiv2019

Epigenetic suppression of interferon lambda receptor expression leads to an enhanced HuNoV replication in vitro

Human norovirus (HuNoV) is the main cause of acute gastroenteritis worldwide yet no therapeutics are currently available. Here, we utilize a human norovirus replicon in epithelial human gastric tumor (HGT) cells to identify host factors involved in promoting or inhibiting HuNoV replication. We observed that an IFN-cured population of replicon-harboring HGT cells (HGT-cured) was enhanced in their ability to replicate transfected HuNoV RNA compared to parental HGT cells, suggesting that differential gene expression in HGT-cured cells created an environment favouring the replication of viral RNA. Microarray analysis was used to identify genes differentially regulated in HGT-NV and HGT-cured compared to parental HGT cells. We found that the IFN lambda receptor alpha (IFNLR1) expression was highly reduced in HGT-NV and HGT-cured cells. All three cell lines responded to exogenous IFN-{beta} by inducing interferon stimulated genes (ISGs), however, HGT-NV and HGT-cured failed to respond to exogenous IFN-{lambda}. Inhibition of DNA methyltransferase activity with 5-aza-2-deoxycytidine partially reactivated IFNLR1 expression in HGT-NV and IFN-cured cells suggesting that host adaptation occurred via epigenetic reprogramming. In line with this observation, ectopic expression of the IFN-{lambda} receptor alpha rescued HGT-NV and HGT-cured cells response to IFN-{lambda}. We conclude that type III IFN is important in inhibiting HuNoV replication in vitro and that the loss of IFNLR1 enhances replication of HuNoV. To the best of our knowledge, this study unravels for the first time epigenetic reprograming of the interferon lambda receptor as a new mechanism of cellular adaptation during long-term RNA virus replication and shows that an endogenous level of interferon lambda signalling is able to control human norovirus replication.

microbiology↗