CYB561A3 is the Key Lysosomal Iron Reductase Required for Burkitt B-cell Growth and Survival

Blood ◽  
2021 ◽  
Author(s):  
Zhonghao Wang ◽  
Rui Guo ◽  
Stephen J Trudeau ◽  
Emma Wolinsky ◽  
Tsliil Ast ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Sub Saharan Africa ◽  
Cell Physiology ◽  
Iron Starvation ◽  
Growth And Survival ◽  
Ferrous Citrate ◽  
Barr Virus ◽  
Epstein Barr ◽  
Sub Saharan

Epstein-Barr virus (EBV) causes endemic Burkitt lymphoma, the leading childhood cancer in sub-Saharan Africa. Burkitt cells retain aspects of germinal center B-cell physiology with MYC-driven B-cell hyperproliferation, yet little is presently known about their iron metabolism. CRISPR/Cas9 analysis highlighted the little studied ferrireductase CYB561A3 as critical for Burkitt proliferation, but not for that of closely related EBV-transformed lymphoblastoid cells or nearly all other Cancer Dependency Map cell lines. Burkitt CYB561A3 knockout induced profound iron starvation, despite ferritinophagy and plasma membrane transferrin upregulation. Elevated concentrations of ascorbic acid, a key CYB561 family electron donor or the labile iron source ferrous citrate rescued Burkitt CYB561A3 deficiency. CYB561A3 knockout caused catastrophic lysosomal and mitochondrial damage and impaired mitochondrial respiration. By contrast, lymphoblastoid B-cells with the transforming EBV latency III program were instead dependent on the STEAP3 ferrireductase. These results highlight CYB561A3 it as an attractive therapeutic Burkitt lymphoma target.

scholarly journals Genetic Subgroups Inform on Pathobiology in Adult and Pediatric Burkitt Lymphoma

2021 ◽  
Author(s):  
Nicole Thomas ◽  
Kostiantyn Dreval ◽  
Daniela S. Gerhard ◽  
Laura K. Hilton ◽  
Jeremy S. Abramson ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Epidemiological Studies ◽  
Sub Saharan Africa ◽  
Driver Mutations ◽  
Barr Virus ◽  
Molecular Features ◽  
Genetic Features ◽  
Epstein Barr

AbstractBurkitt lymphoma (BL) accounts for the majority of pediatric non-Hodgkin lymphomas (NHL) and is relatively rare but significantly more lethal when diagnosed in adults. The global incidence is highest in Sub-Saharan Africa, where Epstein-Barr virus (EBV) positivity is observed in 95% of all tumors. Both pediatric (pBL) and adult (aBL) cases are known to share some driver mutations, for example MYC translocations, which are seen in > 90% of cases. Sequencing efforts have identified many common somatic alterations that cooperate with MYC in lymphomagenesis with approximately 30 significantly mutated genes (SMG) reported thus far. Recent analyses revealed non-coding mutation patterns in pBL that were attributed to aberrant somatic hypermutation (aSHM). We sought to identify genomic and molecular features that may explain clinical disparities within and between aBL and pBL in an effort to delineate BL subtypes that may allow for the stratification of patients with shared pathobiology. Through comprehensive sequencing of BL genomes, we found additional SMGs, including more genetic features that associate with tumor EBV status, and established three new genetic subgroups that span pBL and aBL. Direct comparisons between pBL and aBL revealed only marginal differences and the mutational profiles were consistently better explained by EBV status. Using an unsupervised clustering approach to identify subgroupings within BL and diffuse large B-cell lymphoma (DLBCL), we have defined three genetic subgroups that predominantly comprise BL tumors. Akin to the recently defined DLBCL subgroups, each BL subgroup is characterized by combinations of common driver mutations and non-coding mutations caused by aSHM. Two of these subgroups and their prototypical genetic features (ID3 and TP53) had significant associations with patient outcomes that were different among the aBL and pBL cohorts. These findings highlight not only a shared pathogenesis between aBL and pBL, but also establish genetic subtypes within BL that serve to delineate tumors with distinct molecular features, providing a new framework for epidemiological studies, and diagnostic and therapeutic strategies.

scholarly journals Epstein-Barr Virus-Induced Gene 3 (EBI3): A Novel Diagnosis Marker in Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma

PLoS ONE ◽  
2011 ◽  
Vol 6 (9) ◽  
pp. e24617 ◽  
Author(s):  
Julie Gonin ◽  
Frédérique Larousserie ◽  
Christian Bastard ◽  
Jean-Michel Picquenot ◽  
Jérôme Couturier ◽  
...  
Keyword(s):  
B Cell ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Barr Virus ◽  
Large B Cell Lymphoma ◽  
Epstein Barr ◽  
Large B Cell

scholarly journals Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-cell Growth and Survival

2021 ◽  
Author(s):  
Jin-Hua Liang ◽  
Chong Wang ◽  
Stephanie Pei Tung Yiu ◽  
Bo Zhao ◽  
Rui Guo ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
De Novo ◽  
Cell Mediated Immunity ◽  
Growth And Survival ◽  
Pyrimidine Synthesis ◽  
Barr Virus ◽  
Epstein Barr ◽  
Cns Lymphomas

Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5' triphosphate synthase 1 (CTPS1) suppress cell mediated immunity, resulting in fulminant EBV infection and EBV+ central nervous system (CNS) lymphomas. Since CTP is a critical precursor for DNA, RNA and phospholipid synthesis, this observation raises the question of whether the isozyme CTPS2 or cytidine salvage pathways help meet CTP demand in EBV-infected B-cells. Here, we found that EBV upregulated CTPS1 and CTPS2 with distinct kinetics in newly infected B-cells. While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCL), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes. EBNA2, MYC and non-canonical NF-?B positively regulated CTPS1 expression. CTPS1 depletion impaired EBV lytic DNA synthesis, suggesting that latent EBV may drive pathogenesis with CTPS1 deficiency. Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCL and Burkitt B-cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders. Collectively, our results suggest that CTPS1 and CTPS2 have partially redundant roles in EBV-transformed B-cells and provide insights into EBV pathogenesis with CTPS1 deficiency.

scholarly journals Up-regulation of Lamin A/C Expression in Epstein-Barr Virus Immortalized B Cells and Burkitt Lymphoma Cell Lines of Activated B Cell Phenotype

2016 ◽  
Author(s):  
Ferenc Bánáti ◽  
Anita Koroknai ◽  
Kálmán Szenthe ◽  
Tamás Tereh ◽  
Nóra Kovács ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Cell Phenotype ◽  
Lamin A ◽  
Histone Marks ◽  
Barr Virus ◽  
Epstein Barr

Lamin A, B and C, the nuclear intermediate-filament proteins, play a role in epigenetic regulation. While Lamin B is expressed in all nucleated cells studied, Lamin A/C are transcribed in most somatic cell types except mature B lymphocytes. Since Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with tumorigenic processes and is known to alter the epigenotype of its host cells, we studied the expression of the LMNA gene and its epigenetic marks in EBV-carrying human lymphoid cell lines. We observed a high lamin A/C mRNA and protein expression in EBV-immortalized lymphoblastoid cell lines (LCLs) and in group III Burkitt lymphoma (BL) lines where hypomethylated first exons were observed with activating histone marks. In most cell lines with low promoter activity a highly methylated first exon could be detected. Our data showed that methylation of the first exon of LMNA was associated with the downregulation of LMNA expression whereas euchromatic histone marks were enriched at active LMNA promoters in EBV-immortalized LCLs. These data suggest a role for viral latency products to activate LMNAp in EBV-infected latency type III B cells in vitro. Expression of lamin A/C may contribute to the establishment of activated B cell phenotype that needs further explorations.

scholarly journals Kaposi Sarcoma-Associated Herpesvirus Infection and Endemic Burkitt Lymphoma

2020 ◽  
Vol 222 (1) ◽  
pp. 111-120 ◽  
Author(s):  
Peter O Oluoch ◽  
Cliff I Oduor ◽  
Catherine S Forconi ◽  
John M Ong’echa ◽  
Christian Münz ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Kaposi Sarcoma ◽  
Plasmodium Falciparum Malaria ◽  
Dual Infection ◽  
Potential Effect ◽  
Sub Saharan Africa ◽  
Healthy Children ◽  
Barr Virus ◽  
Epstein Barr ◽  
Antibody Levels

Abstract Background Endemic Burkitt lymphoma (eBL) is associated with Epstein-Barr virus (EBV) and Plasmodium falciparum malaria coinfections. However, the role of Kaposi sarcoma-associated herpesvirus (KSHV), also endemic in Africa, has not been evaluated as a cofactor in eBL pathogenesis. Methods Multiplexed seroprofiles for EBV, malaria, and KSHV were generated for 266 eBL patients, 78 non-eBL cancers, and 202 healthy children. KSHV and EBV loads were quantified by PCR. Results KSHV seroprevalence did not differ by study group but was associated with age. Seropositivity, defined by K8.1/LANA or in combination with 5 other KSHV antigens (ORF59, ORF65, ORF61, ORF38, and K5) was associated with antimalarial antibody levels to AMA1 (odds ratio [OR], 2.41, P < .001; OR, 2.07, P < .001) and MSP1 (OR, 2.41, P = .0006; OR, 5.78, P < .001), respectively. KSHV loads did not correlate with antibody levels nor differ across groups but were significantly lower in children with detectable EBV viremia (P = .014). Conclusions Although KSHV-EBV dual infection does not increase eBL risk, EBV appears to suppress reactivation of KSHV while malaria exposure is associated with KSHV infection and/or reactivation. Both EBV and malaria should, therefore, be considered as potential effect modifiers for KSHV-associated cancers in sub-Saharan Africa.

scholarly journals Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth and Survival

mBio ◽  
2021 ◽  
Author(s):  
Jin Hua Liang ◽  
Chong Wang ◽  
Stephanie Pei Tung Yiu ◽  
Bo Zhao ◽  
Rui Guo ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
De Novo ◽  
Cell Mediated Immunity ◽  
Growth And Survival ◽  
Pyrimidine Synthesis ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr ◽  
Cns Lymphomas

Epstein-Barr virus (EBV) is associated with 200,000 cancers annually, including B-cell lymphomas in immunosuppressed hosts. Hypomorphic mutations of the de novo pyrimidine synthesis pathway enzyme cytidine 5′ triphosphate synthase 1 (CTPS1) suppress cell-mediated immunity, resulting in fulminant EBV infection and EBV + central nervous system (CNS) lymphomas.

scholarly journals Transfection of the c-myc oncogene into normal Epstein-Barr virus-harboring B cells results in new phenotypic and functional features resembling those of Burkitt lymphoma cells and normal centroblasts.

1995 ◽  
Vol 181 (2) ◽  
pp. 699-711 ◽  
Author(s):  
G Cutrona ◽  
M Ulivi ◽  
F Fais ◽  
S Roncella ◽  
M Ferrarini
Keyword(s):  
B Cells ◽  
Serum Concentration ◽  
B Cell ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
Transfected Cells ◽  
Barr Virus ◽  
Myc Gene ◽  
Functional Features ◽  
Epstein Barr

Activated c-myc gene was introduced into the cells of three normal Epstein-Barr virus (EBV)-positive lymphoblastoid B cell lines (LCL). The cells were monitored for the appearance of new phenotypic and functional features compared with the control LCL cells transfected with plasmid that did not contain the c-myc gene. The LCL-expressing c-myc constitutively did not arrest growth in low serum concentration. However, the cell number in the cultures failed to increase because of substantial cell death. Death was due to apoptosis as demonstrated by flow cytometric analysis of propidium iodide-stained cells, by typical DNA laddering in gel electrophoresis, and by the inspection of Giemsa-stained cell smears. Apoptosis was also induced by exposing the transfected cells to antibodies directed to the immunoglobulin mu chain (a-mu-ab) irrespective of the serum concentration in the culture. Exposure of the cells to CD40 ligand (CD40L) or CD40 monoclonal antibody prevented cell apoptosis. Upon transfection with c-myc, the LCL cells acquired a vacuolated morphology that was never observed in control cells. Moreover, the expression of CD10 and CD38 was upregulated, while that of CD39 and especially CD23 was downregulated. Unlike that observed in certain Burkitt lymphoma (BL) cell lines that share the same surface phenotype (CD10+CD38+CD23-CD39-), the c-myc-transfected cells expressed lymphocyte function-associated (LFA) 1, LFA-3, and intercellular adhesion molecule 1 and grew in large clumps rather than single-cell layers. Expression of CD10 and CD38 was particularly evident on the cells undergoing apoptosis, thus suggesting a correlation between the presence of these markers and the apoptotic process. Cells placed in conditions favoring in vitro apoptosis displayed downregulation of Bcl-2 protein. Bcl-2 expression was, however, upregulated when the cells were exposed to CD40L. These data indicate that the B cells expressing c-myc constitutively acquire some of the features of normal centroblasts and of BL cells, including the expression of CD10 and CD38, and the propensity to undergo apoptosis, which can be prevented by exposure to CD40L. Therefore, these cells can serve as a model system to study both BL lymphomagenesis as well as the process of B cell selection occurring in the germinal centers.

Epstein-Barr virus nuclear antigen 2 induces FcRH5 expression through CBF1

Blood ◽  
2006 ◽  
Vol 107 (11) ◽  
pp. 4433-4439 ◽  
Author(s):  
Joanne Mohan ◽  
Jessica Dement-Brown ◽  
Sabine Maier ◽  
Tomoko Ise ◽  
Bettina Kempkes ◽  
...  
Keyword(s):  
Dna Binding ◽  
B Cell ◽  
Burkitt Lymphoma ◽  
Epstein Barr Virus ◽  
De Novo ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr ◽  
Chromosome 1Q21

AbstractFc-receptor homolog 5 (FcRH5) is a recently identified B-cell membrane protein of unknown function. In Burkitt lymphoma cell lines with chromosome 1q21 abnormalities, FcRH5 expression is deregulated, implicating FcRH5 in lymphomagenesis. Epstein-Barr virus infects and immortalizes B cells, and is implicated in the etiology of several tumors of B-cell origin. Overexpression of genes located on 1q21-25 has been proposed as a surrogate for Epstein-Barr virus in Burkitt lymphoma. We now report that Epstein-Barr virus nuclear antigen 2 (EBNA2) markedly induces the expression of the FcRH5 gene, encoded on chromosome 1q21. Induction occurred in the absence of other viral proteins and did not require de novo protein synthesis. EBNA2 lacks a DNA-binding domain and can target responsive genes through the host DNA binding protein CBF1. We show that induction of FcRH5 by EBNA2 is strictly CBF1 dependent, as it was abolished in CBF1-deficient cells. Accordingly, EBNA2 targeted CBF1 binding sites present in the FcRH5 promoter in vivo, as detected by chromatin immunoprecipitation. These results identify FcRH5 as a novel, direct target of EBNA2 that may contribute to the development of Epstein-Barr virus–associated tumors.

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