scholarly journals v-rel Induces ectopic expression of an adhesion molecule, DM-GRASP, during B-lymphoma development.

1995 ◽  
Vol 15 (3) ◽  
pp. 1806-1816 ◽  
Author(s):  
G Zhang ◽  
C Slaughter ◽  
E H Humphries
Keyword(s):  
Amino Acid ◽  
B Cell ◽  
Adhesion Molecule ◽  
Mononuclear Cells ◽  
Ectopic Expression ◽  
Pcr Amplification ◽  
Immunoglobulin Superfamily ◽  
B Cell Lymphomas ◽  
In Vitro Proliferation

In an effort to identify aberrantly expressed genes in v-rel-induced tumors, monoclonal antibodies were developed that reacted selectively with avian B-cell tumors. One antibody, HY78, immunoprecipitated a 120-kDa glycoprotein (p120) from cells that express v-rel. N-terminal amino acid sequencing of p120 identified a 27-amino-acid sequence that is also present in DM-GRASP, an adhesion molecule belonging to the immunoglobulin superfamily. Evidence from tissue distribution, immunological cross-reaction, PCR amplification, cDNA cloning, and DNA sequence shows that p120 is indeed DM-GRASP. Northern (RNA) analysis using a probe from the DM-GRASP gene identified a 5.3-kb transcript in mRNA from bursa, thymus, and brain as well as from v-rel-induced B-cell lymphomas but not from bursal B cells. The induction of this protein by v-rel during the development of bursal B-cell lymphomas appears, therefore, to be ectopic in nature. Overexpression of v-rel or c-rel in chicken embryonic fibroblasts, B-cell lines, and spleen mononuclear cells induces the expression of DM-GRASP. The ratio of DM-GRASP to v-Rel was fivefold higher than that of DM-GRASP/c-Rel in a B-cell line, DT95. Interestingly, the presence of HY78 antibody inhibits the in vitro proliferation of v-rel-transformed cells but not cells that immortalized by myc. These data suggest that DM-GRASP is one of the genes induced during v-rel-mediated tumor development and that DM-GRASP may be involved in the growth of v-rel tumor cells.

Development and characterization of APRIL antagonistic monoclonal antibodies for treatment of B-cell lymphomas

Blood ◽  
2011 ◽  
Vol 117 (25) ◽  
pp. 6856-6865 ◽  
Author(s):  
Marco Guadagnoli ◽  
Fiona C. Kimberley ◽  
Uyen Phan ◽  
Katherine Cameron ◽  
Paul M. Vink ◽  
...  
Keyword(s):  
B Cell ◽  
Family Member ◽  
Lymphocytic Leukemia ◽  
Growth Promoter ◽  
B Cell Lymphomas ◽  
B Cell Malignancies ◽  
In Vitro Proliferation ◽  
Iga Production ◽  
Human B Cell

Abstract APRIL (A proliferation-inducing ligand) is a TNF family member that binds two TNF receptor family members, TACI and BCMA. It shares these receptors with the closely related TNF family member, B-cell activating factor (BAFF). Contrary to BAFF, APRIL binds heparan sulfate proteoglycans (HSPGs), which regulates cross-linking of APRIL and efficient signaling. APRIL was originally identified as a growth promoter of solid tumors, and more recent evidence defines APRIL also as an important survival factor in several human B-cell malignancies, such as chronic lymphocytic leukemia (CLL). To target APRIL therapeutically, we developed two anti–human APRIL antibodies (hAPRIL.01A and hAPRIL.03A) that block APRIL binding to BCMA and TACI. Their antagonistic properties are unique when compared with a series of commercially available monoclonal anti–human APRIL antibodies as they prevent in vitro proliferation and IgA production of APRIL-reactive B cells. In addition, they effectively impair the CLL-like phenotype of aging APRIL transgenic mice and, more importantly, block APRIL binding to human B-cell lymphomas and prevent the survival effect induced by APRIL. We therefore conclude that these antibodies have potential for further development as therapeutics to target APRIL-dependent survival in B-cell malignancies.

Malignant hematopoietic cell lines: In vitro models for the study of primary mediastinal B-cell lymphomas

2015 ◽  
Vol 39 (1) ◽  
pp. 18-29 ◽  
Author(s):  
Hans G. Drexler ◽  
Stefan Ehrentraut ◽  
Stefan Nagel ◽  
Sonja Eberth ◽  
Roderick A.F. MacLeod
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
In Vitro Models ◽  
Hematopoietic Cell ◽  
B Cell Lymphomas ◽  
Hematopoietic Cell Lines

scholarly journals Ectopic expression of transcription factor BATF3 induces B-cell lymphomas in a murine B-cell transplantation model

Oncotarget ◽  
2018 ◽  
Vol 9 (22) ◽  
pp. 15942-15951 ◽  
Author(s):  
Christian Weiser ◽  
Mina V. Petkova ◽  
Benjamin Rengstl ◽  
Claudia Döring ◽  
Dorothee von Laer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cell ◽  
Cell Transplantation ◽  
Ectopic Expression ◽  
B Cell Lymphomas ◽  
Transplantation Model

Transduction of inflammation from peripheral immune cells to the hippocampus induces neuronal hyperexcitability mediated by Caspase-1 activation

2020 ◽  
Author(s):  
Tarek Shaker ◽  
Bidisha Chattopadhyaya ◽  
Bénédicte Amilhon ◽  
Graziella Di Cristo ◽  
Alexander G. Weil
Keyword(s):  
Mononuclear Cells ◽  
Culture Media ◽  
Ectopic Expression ◽  
Peripheral Inflammation ◽  
Potential Contribution ◽  
Inflammation Markers ◽  
Peripheral Blood Mononuclear ◽  
Caspase 1 ◽  
Therapeutic Benefits

Abstract Background Recent studies report infiltration of peripheral blood mononuclear cells (PBMCs) into the central nervous system (CNS) in epileptic disorders, suggestive of a potential contribution of PBMC extravasation to the generation of seizures. Nevertheless, the underlying mechanisms involved in PBMC infiltrates promoting neuronal predisposition to ictogenesis remain unclear. Therefore, we developed an in vitro model mimicking PBMC infiltration into the brain in order to investigate potential transduction of inflammatory signals from PBMCs to the CNS.MethodsTo establish our model, we first extracted PBMCs from rat spleen, then, we immunologically primed PBMCs with lipopolysaccharide (LPS), followed by immunological activation with Nigericin. Thereafter, we cultured PBMCs on top of organotypic cortico-hippocampal brain slice cultures (OCHSCs) derived from the same rat, and compared PBMC-OCHSC co-cultures to OCHSCs exposed to PBMCs in the culture media. Also, we targeted a potential molecular pathway underlying transduction of peripheral inflammation to OCHSCs by incubating OCHSCs with the Caspase-1 inhibitor VX-765 prior to co-culturing PBMCs with OCHSCs. After 24 hours, we immunohistochemically analyzed inflammation markers in the cortex and the hippocampus. In addition, we performed whole-cell patch-clamp recordings in cortical layer II/III and hippocampal CA1 pyramidal neurons.ResultsIn the cortex, co-culturing immunoreactive PBMCs treated with LPS + Nigericin on top of OCHSCs induced ectopic expression of inflammation markers and enhanced neuronal excitation. In contrast, no excitability changes were detected after adding primed PBMCs, i.e. treated with LPS only, to OCHSCs. Strikingly, in the hippocampus, both immunoreactive and primed PBMCs elicited similar pro-inflammatory and pro-excitatory effects. However, when immunoreactive and primed PBMCs were cultured in the media separately from OCHSCs, only immunoreactive PBMCs gave rise to neuroinflammation and hyperexcitability in the hippocampus, whereas primed PBMCs failed to produce any significant changes. Finally, VX-765 application to OCHSCs, co-cultured with either immunoreactive or primed PBMCs, protected them from neuroinflammation and hippocampal hyperexcitability.ConclusionsOur study shows a higher susceptibility of the hippocampus to peripheral inflammation as compared to the cortex, mediated via Caspase-1-dependent signaling pathways. Thus, our findings suggest that Caspase-1 inhibition may potentially provide therapeutic benefits during hippocampal neuroinflammation and hyperexcitability secondary to peripheral innate immunity.

A-myb rescues murine B-cell lymphomas from IgM-receptor–mediated apoptosis through c-myctranscriptional regulation

Blood ◽  
2000 ◽  
Vol 96 (3) ◽  
pp. 1013-1020 ◽  
Author(s):  
Marcello Arsura ◽  
Claudia S. Hofmann ◽  
Josee Golay ◽  
Martino Introna ◽  
Gail E. Sonenshein
Keyword(s):  
B Cell ◽  
Cell Survival ◽  
Ectopic Expression ◽  
Cell Types ◽  
B Cell Lymphomas ◽  
Myb Gene ◽  
B Cell Survival ◽  
Wehi 231 ◽  
Myc Gene ◽  
Human B Cell

Abstract A-myb is a member of the myb family of transcription factors, which regulates proliferation, differentiation, and apoptosis of hematopoietic cells. A-Myb expression is normally restricted to the proliferating B-cell centroblasts and transgenic mice overexpressing A-myb displayed enhanced hyperplasia of the lymph nodes. Because A-Myb is highly expressed in several subtypes of human B-cell neoplasias, we sought to determine whether the A-myb gene promoted proliferation and survival of B lymphocytes, using the WEHI 231 and CH33 murine B-cell lymphomas as models. Here, we show that ectopic expression of A-mybrescues WEHI 231 and CH33 cells from growth arrest and apoptosis induced by anti-IgM treatment. Previously, we demonstrated an essential role of the c-myc gene in promoting cell survival of WEHI 231 cells in response to a variety of apoptotic stimuli. Furthermore, we and others have shown that the c-myc gene is potently transactivated by A-Myb in several cell types. Thus, we sought to determine whether c-Myc would mediate the A-Myb antiapoptotic effect in B cells. Here we show that ectopic expression of A-myb leads to maintenance of c-myc expression, and that expression of antisense c-myc RNA ablates A-Myb–mediated survival signals. Thus, these findings strongly implicate the A-myb gene in the regulation of B-cell survival and confirm the c-myc gene as one of the downstream targets of A-myb in these cells. Overall, our observation suggests that A-mybexpression may be relevant to the pathology of human B-cell neoplasias.

scholarly journals Targeting N-myristoylation for therapy of B-cell lymphomas

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Erwan Beauchamp ◽  
Megan C. Yap ◽  
Aishwarya Iyer ◽  
Maneka A. Perinpanayagam ◽  
Jay M. Gamma ◽  
...  
Keyword(s):  
B Cell ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Cell Receptor ◽  
B Cell Lymphomas ◽  
Cancer Cell Death ◽  
Anti Cancer ◽  
Xenograft Models ◽  
Patients Experience

Abstract Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, is critical for membrane targeting and cell signaling. Because cancer cells often have increased N-myristoyltransferase (NMT) expression, NMTs were proposed as anti-cancer targets. To systematically investigate this, we performed robotic cancer cell line screens and discovered a marked sensitivity of hematological cancer cell lines, including B-cell lymphomas, to the potent pan-NMT inhibitor PCLX-001. PCLX-001 treatment impacts the global myristoylation of lymphoma cell proteins and inhibits early B-cell receptor (BCR) signaling events critical for survival. In addition to abrogating myristoylation of Src family kinases, PCLX-001 also promotes their degradation and, unexpectedly, that of numerous non-myristoylated BCR effectors including c-Myc, NFκB and P-ERK, leading to cancer cell death in vitro and in xenograft models. Because some treated lymphoma patients experience relapse and die, targeting B-cell lymphomas with a NMT inhibitor potentially provides an additional much needed treatment option for lymphoma.

scholarly journals Co-infusion of high-dose haploidentical donor cells and CD19-targeted CART cells achieves complete remission, successful donor engraftment and significant CART amplification in advanced ALL

2020 ◽  
Vol 12 ◽  
pp. 175883592092760 ◽  
Author(s):  
Changlin Yu ◽  
Bo Cai ◽  
Yao Wang ◽  
Zhiqiang Wu ◽  
Kaixun Hu ◽  
...  
Keyword(s):  
Complete Remission ◽  
B Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
High Dose ◽  
Peripheral Blood Mononuclear ◽  
Grade Ii

Autologous CD19-targeted chimeric antigen receptor-modified T cells (CD19-CART) remarkably improved the outcome of patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, the application and outcomes of allogeneic CART cells is still uncertain. Two patients with advanced B-ALL were enrolled to receive a co-infusion of high-dose human leukocyte antigen-haploidentical donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells (GPBMCs; 21.01–25.34 × 108/kg) and the same donor-derived CD19-targeted CART cells (8.44–22.19 × 106/kg) without additional in vitro gene-editing following a reinduction chemotherapy as precondition. They achieved complete remission and full donor chimerism (FDC) with ongoing 20- and 4-month leukemia-free survival. A significant amplification of donor CART cells was detected in peripheral blood and/or cerebrospinal fluid and was associated with the formation of FDC. The highest amount of copies of the donor CART cells reached 4962 per µg of genomic DNA (gDNA) and 2449 per µg of gDNA, and the longest persistence was 20 months associated with B cell aplasia. Two patients experienced Grade II or III cytokine release syndromes and developed controllable Grade II intestinal acute graft-versus-host disease (GVHD) or limited chronic oral GVHD. High-dose donor GPBMC infusion may enhance amplification and persistence of haploidentical CD19-targeted CART cells, suggesting an alternative therapy for advanced B-ALL patients.

scholarly journals Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells

2020 ◽  
Author(s):  
Kang Wang ◽  
Zhengyang Zhang ◽  
Hsiang-i Tsai ◽  
Yanfang Liu ◽  
Jie Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Amino Acid ◽  
Cancer Cells ◽  
Ectopic Expression ◽  
Branched Chain Amino Acid ◽  
Pancreatic Cancer Cells ◽  
Key Enzyme ◽  
Branched Chain

Abstract Ferroptosis, a form of iron-dependent cell death driven by cellular metabolism and iron-dependent lipid peroxidation, has been implicated as a tumor-suppressor function for cancer therapy. Recent advance revealed that the sensitivity to ferroptosis is tightly linked to numerous biological processes, including metabolism of amino acid and the biosynthesis of glutathione. Here, by using a high-throughput CRISPR/Cas9-based genetic screen in HepG2 hepatocellular carcinoma cells to search for metabolic proteins inhibiting ferroptosis, we identified a branched-chain amino acid aminotransferase 2 (BCAT2) as a novel suppressor of ferroptosis. Mechanistically, ferroptosis inducers (erastin, sorafenib, and sulfasalazine) activated AMPK/SREBP1 signaling pathway through iron-dependent ferritinophagy, which in turn inhibited BCAT2 transcription. We further confirmed that BCAT2 as the key enzyme mediating the metabolism of sulfur amino acid, regulated intracellular glutamate level, whose activation by ectopic expression specifically antagonize system Xc– inhibition and protected liver and pancreatic cancer cells from ferroptosis in vitro and in vivo. On the contrary, direct inhibition of BCAT2 by RNA interference, or indirect inhibition by blocking system Xc– activity, triggers ferroptosis. Finally, our results demonstrate the synergistic effect of sorafenib and sulfasalazine in downregulating BCAT2 expression and dictating ferroptotic death, where BCAT2 can also be used to predict the responsiveness of cancer cells to ferroptosis-inducing therapies. Collectively, these findings identify a novel role of BCAT2 in ferroptosis, suggesting a potential therapeutic strategy for overcoming sorafenib resistance.

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