scholarly journals Proteomic-Based Analysis of Hypoxia- and Physioxia-Responsive Proteins and Pathways in Diffuse Large B-Cell Lymphoma

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 2025
Author(s):  
Kamila Duś-Szachniewicz ◽  
Katarzyna Gdesz-Birula ◽  
Krzysztof Zduniak ◽  
Jacek R. Wiśniewski
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
Enrichment Analysis ◽  
B Cell Lymphoma ◽  
Pathway Enrichment Analysis ◽  
Large B Cell Lymphoma ◽  
Long Time ◽  
Proteome Changes ◽  
Large B Cell

Hypoxia is a common feature in most tumors, including hematological malignancies. There is a lack of studies on hypoxia- and physioxia-induced global proteome changes in lymphoma. Here, we sought to explore how the proteome of diffuse large B-cell lymphoma (DLBCL) changes when cells are exposed to acute hypoxic stress (1% of O2) and physioxia (5% of O2) for a long-time. A total of 8239 proteins were identified by LC–MS/MS, of which 718, 513, and 486 had significant changes, in abundance, in the Ri-1, U2904, and U2932 cell lines, respectively. We observed that changes in B-NHL proteome profiles induced by hypoxia and physioxia were quantitatively similar in each cell line; however, differentially abundant proteins (DAPs) were specific to a certain cell line. A significant downregulation of several ribosome proteins indicated a translational inhibition of new ribosome protein synthesis in hypoxia, what was confirmed in a pathway enrichment analysis. In addition, downregulated proteins highlighted the altered cell cycle, metabolism, and interferon signaling. As expected, the enrichment of upregulated proteins revealed terms related to metabolism, HIF1 signaling, and response to oxidative stress. In accordance to our results, physioxia induced weaker changes in the protein abundance when compared to those induced by hypoxia. Our data provide new evidence for understanding mechanisms by which DLBCL cells respond to a variable oxygen level. Furthermore, this study reveals multiple hypoxia-responsive proteins showing an altered abundance in hypoxic and physioxic DLBCL. It remains to be investigated whether changes in the proteomes of DLBCL under normoxia and physioxia have functional consequences on lymphoma development and progression.

Establishment of a cell line from a chemotherapy resistant diffuse large B-cell lymphoma

2007 ◽  
Vol 48 (5) ◽  
pp. 1038-1041 ◽  
Author(s):  
Mattias Berglund ◽  
Ulf Thunberg ◽  
Marie Fridberg ◽  
Anette Gjörloff Wingren ◽  
Joachim Gullbo ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
A Cell ◽  
Large B Cell

scholarly journals Combination Benefit of Capivasertib and Venetoclax in Preclinical Models of Diffuse Large B-Cell Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1870-1870
Author(s):  
Brandon Willis ◽  
India Neveras ◽  
Hannah Dry ◽  
Wendan Xu ◽  
Yang Li ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Mouse Models ◽  
Cell Lines ◽  
Stock Options ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Growth Inhibition ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy among adults and despite approximately 65% of patients with DLBCL being cured with RCHOP therapy, nonresponsive and relapsed patients have inadequate treatment options, highlighting the importance for innovative treatment regimens. Blockade of B-cell receptor (BCR) downstream signaling components with various targeted agents is emerging as a clinically tractable treatment strategy across multiple B-cell malignancies. Protein Kinase B (AKT) signaling downstream of the BCR complex has been shown to be a central node in germinal center B-cell (GCB) DLBCL and the potent, selective inhibitor of AKT1, AKT2, AKT3, capivasertib, currently being evaluated in multiple clinical trials by targeting AKT-driven solid cancers, has been shown to induce apoptosis in a subset of GCB-DLBCL cell lines and cause tumor stasis in xenograft mouse models (Erdman et al., 2017). Since the monotherapy capivasertib responses in GCB DLBCL models are partial and lack durability, we hypothesized a combination approach could deliver even greater therapeutic benefit. To identify optimal partners, we conducted a capivasertib centric in vitro combination screen with specific with BH3 family members across a panel of 15 DLBCL cell lines, which revealed a synergistically active combination with the BCL2 inhibitor, venetoclax which is currently being evaluated in DLBCL. The activity was specifically enhanced in cell lines of the GCB subtype, with 4 PTEN del and 2 PTEN wt cell line models showing combination benefit. To determine the ability of this combination to drive stronger and durable responses, we assessed capivasertib and ventoclax activity in xenograft mouse models using two GCB-DLBCL cell line lines, SUDHL4 (PTEN wt) and WSU-DLCL2 (PTEN del). Oral administration of either monotherapy capivasertib (130 mg/kg BID, 4-day on/3-day off) or venetoclax (100 mg/kg QD) provided partial tumor growth inhibition (capivasertib TGI = 74% in SUDHL4 and 29% in WSU-DLCL2, and venetoclax TGI = 46% in SUDHL4 and 0% in WSU-DLCL2), whereas the combination of capivasertib and venetoclax both on a 4-day on/3-day off schedule produced complete tumor regression (100% regression) in both xenograft GCB cell line models during the dosing period. Notably, in both xenograft models all mice (5/5 per model) remained tumor free for at least 30 days following dosing cessation demonstrating high durability of response for the combination. Additionally, this combination is currently being evaluated in clinically relevant GCB and non-GCB PDX mouse models. Taken together, our results provide preclinical evidence for the rational combination of AKT and BCL-2 blockade with capivasertib and venetoclax respectively in patients with relapsed/refractory GCB-DLBCL. Disclosures Willis: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Neveras: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Dry: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Mongeon: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Rosen: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Mettetal: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options. Barry: AstraZeneca: Current Employment, Other: may hold equity, stock, or stock options.

Establishment of a novel CD20 negative mature B-cell line, WILL2, from a CD20 positive diffuse large B-cell lymphoma patient treated with rituximab

2009 ◽  
Vol 89 (3) ◽  
pp. 400-402 ◽  
Author(s):  
Takashi Sonoki ◽  
Yaqiong Li ◽  
Setsuko Miyanishi ◽  
Hirokazu Nakamine ◽  
Nobuyoshi Hanaoka ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Patient ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals VR09 Cell Line: An EBV-Positive Lymphoblastoid Cell Line with In Vivo Characteristics of Diffuse Large B Cell Lymphoma of Activated B-Cell Type

PLoS ONE ◽  
2012 ◽  
Vol 7 (12) ◽  
pp. e52811 ◽  
Author(s):  
Ilaria Nichele ◽  
Alberto Zamò ◽  
Anna Bertolaso ◽  
Francesco Bifari ◽  
Martina Tinelli ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Lymphoblastoid Cell Line ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Type ◽  
Large B Cell Lymphoma ◽  
Large B Cell

A Novel B-cell Line (U-2932) Established from a Patient with Diffuse Large B-cell Lymphoma Following Hodgkin Lymphoma

2002 ◽  
Vol 43 (11) ◽  
pp. 2179-2189 ◽  
Author(s):  
Rose-Marie Amini ◽  
Mattias Berglund ◽  
Richard Rosenquist ◽  
Anne von Heideman ◽  
Svetlana Lagercrantz ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Subtype-specific addiction of the activated B-cell subset of diffuse large B-cell lymphoma to FOXP1

2016 ◽  
Vol 113 (5) ◽  
pp. E577-E586 ◽  
Author(s):  
Joseph D. Dekker ◽  
Daechan Park ◽  
Arthur L. Shaffer ◽  
Holger Kohlhammer ◽  
Wei Deng ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Target Genes ◽  
Cell Lymphoma ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Highly Correlated ◽  
Dlbcl Subtype ◽  
Large B Cell

High expression of the forkhead box P1 (FOXP1) transcription factor distinguishes the aggressive activated B cell (ABC) diffuse large B-cell lymphoma (DLBCL) subtype from the better prognosis germinal center B-cell (GCB)-DLBCL subtype and is highly correlated with poor outcomes. A genetic or functional role for FOXP1 in lymphomagenesis, however, remains unknown. Here, we report that sustained FOXP1 expression is vital for ABC-DLBCL cell-line survival. Genome-wide analyses revealed direct and indirect FOXP1 transcriptional enforcement of ABC-DLBCL hallmarks, including the classical NF-κB and MYD88 (myeloid differentiation primary response gene 88) pathways. FOXP1 promoted gene expression underlying transition of the GCB cell to the plasmablast—the transient B-cell stage targeted in ABC-DLBCL transformation—by antagonizing pathways distinctive of GCB-DLBCL, including that of the GCB “master regulator,” BCL6 (B-cell lymphoma 6). Cell-line derived FOXP1 target genes that were highly correlated with FOXP1 expression in primary DLBCL accurately segregated the corresponding clinical subtypes of a large cohort of primary DLBCL isolates and identified conserved pathways associated with ABC-DLBCL pathology.

scholarly journals Establishment and characterization of a novel MYC/BCL2 “double-hit” diffuse large B cell lymphoma cell line, RC

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Lan V. Pham ◽  
Gary Lu ◽  
Archito T. Tamayo ◽  
Juan Chen ◽  
Pramoda Challagundla ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cell ◽  
Lymphoma Cell Line ◽  
Large B Cell Lymphoma ◽  
Double Hit ◽  
Large B Cell

scholarly journals New Molecular and Therapeutic Insights into Canine Diffuse Large B Cell Lymphoma Elucidates the Role of the Dog As a Model for Human Disease

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4173-4173
Author(s):  
Luca Aresu ◽  
Serena Ferraresso ◽  
Laura Marconato ◽  
Luciano Cascione ◽  
Sara Napoli ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Clinical Outcome ◽  
B Cell ◽  
Cell Line ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rna Seq ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background. Diffuse large B-cell lymphoma (DLBCL) is the commonest lymphoma in both humans and dogs. Canine DLBCL (cDLBCL) is considered an ideal comparative model for drug development, but a complete genomic characterization of this tumor is still lacking. In this study, we report an integrated analysis to comprehensively define the molecular mechanisms of cDLBCL and possible associations with clinical outcome. Methods. Fifty cDLBCLs were analyzed by RNA-Seq, methyl-CpG-binding sequencing and array comparative genomic hybridization. Normal B-cells derived from lymph nodes of 11 healthy dogs were used as controls.Additionally, immunohistochemistry, in vitroand in vivoexperiments were performed as validation analyses. Results.Compared to normal B-cells, cDLBCL showed a marked up-regulation of genes involved in the PI3K/mTOR and NF-κB pathways, including several TLRs in association with MYD88, indicating mechanisms similar to the human activated B cell-like subtype DLBCL. Both RNA-Seq and methylation sequencing led to the identification of two groups of cDLBCLs bearing different clinical outcome. The two groups did not overlap with the human germinal center B-cell (GCB) and the activated B-cell-like (ABC) DLBCL subtypes or the human DLBCL consensus clusters. The dogs with the poorest outcome presented a signature largely defined by markers of T-cell-mediated immune responses, with a high expression of PDL-1, PD-1 and CTLA-4, also validated in an independent cohort of cDLBCL by immunohistochemistry. These data provide a strong rationale for the use of cDLBCL to study immune checkpoint modulators. The observed high expression of PI3K/mTOR pathway genes was confirmed and validated achieving a clear anti-tumor activity with the use of the PI3K-delta inhibitor idelalisib and of the novel dual PI3K/mTOR inhibitor bimiralisib in the cDLBCL cell line CLBL-1. The cDLBCLs showed an up-regulation of MYC and of its targets, sustained by recurrent gains in the chromosome 13, where the oncogene is located, in approximately half of the cases. Thus, we have exposed the cDLBCL cell line CLBL-1 to the BET inhibitor birabresib (OTX015) and to the BRD4 degrader MZ1. Both compounds caused a significant reduction in the proliferation of tumor cells, and this effect was stronger especially with the second compound. Exposure to MZ1 determined an important downregulation of MYC and also of LIN28B, the most overexpressed transcript in cDLBCL when compared to controls. While LIN28B does not seem to be a relevant gene for human DLBCL, its overexpression causes murine T-cell lymphomas (Beachy et al, Blood 2011), and there is a direct association of MYC with LIN28B promoter resulting in transcriptional transactivation (Chang et al, PNAS 2009). Here, LIN28B genetic silencing in the CLBL-1 lead to a reduction in cell growth, opening new therapeutic target perspectives in canine lymphoma. Conclusions. We have reported the first large next generation sequencing study investigating the cDLBCL transcriptome, methylome and the genome-wide CNVs. We identified deregulated pathways and individual transcripts providing therapeutic targets, including an immune-related signature affecting the outcome of a subgroup of cDLBCL. Our data sustain the use of cDLBCL as comparative models for human DLBCL but also highlight differences that must be kept in consideration. Disclosures Hillmann: PIQUR Therapeutics AG: Employment. Wymann:PIQUR Therapeutics AG: Employment, Equity Ownership, Patents & Royalties.

scholarly journals NEK2 Promotes Cell Proliferation and Glycolysis by Regulating PKM2 Abundance via Phosphorylation in Diffuse Large B-Cell Lymphoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Lingna Zhou ◽  
Liya Ding ◽  
Yuqi Gong ◽  
Jing Zhao ◽  
Jing Zhang ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Affinity Purification ◽  
Enrichment Analysis ◽  
B Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Lymphoid Tissues ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most frequent and commonly diagnosed subtype of NHL, which is characterized by high heterogeneity and malignancy, and most DLBCL patients are at advanced stages. The serine/threonine kinase NEK2 (NIMA-related kinase 2), a member of NIMA-related kinase (NEK) family that regulates cell cycle, is upregulated in a variety of malignancies, including diffuse large B-cell lymphoma. However, the role and underlying mechanisms of NEK2 in DLBCL have seldom been discussed. In this study, we identified that NEK2 is upregulated in DLBCL compared to normal lymphoid tissues, and overexpression of NEK2 predicted a worse prognosis of DLBCL patients. Gene set enrichment analysis indicates that NEK2 might participate in regulating glycolysis. Knockdown of NEK2 inhibited growth and glycolysis of DLBCL cells. The interaction between NEK2 and PKM2 was discovered by tandem affinity purification and then was confirmed by immunofluorescence staining, coimmunoprecipitation, and immunoprecipitation. NEK2 bounds to PKM2 and regulates PKM2 abundance via phosphorylation, which increases PKM2 stability. The xenograft tumor model checks the influence of NEK2 on tumor growth in vivo. Thus, NEK2 could be the novel biomarker and target of DLBCL, which remarkably ameliorates the diagnosis and treatment of DLBCL.

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