CD 80 and CD 86 Expression, Clinical Implications Are Cancer Dependent as Revealed Through Pan-cancer Analysis

BackgroundCluster of Differentiation 80 and CD 86 can also be called B7-1 and B7-2 respectively. They are proteins fundamentally expressed on antigen-presenting cells (APCs), including induced dendritic cells (IDCs), langerhans cells, germinal center dendritic cells (GCDCs), activated monocytes, macrophages and B-cells. They are considered to be a possible therapeutic target and biomarker of great significance. However, there are still inconsistent pieces of information and their clinical importance is yet to be established. MethodsHere we investigated CD 80 and 86 as biomarkers by utilizing several large genomic data collections. (The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Quantitative proteomics Cancer cell line Encyclopedia Genotype-Tissue Expression,) and analyzed CD 80 and CD 86 expression in thousands of normal and cancer samples and cell lines along with their clinical survival analysis.ResultsThis study presented that CD 86 was expressed more in post-treatment blood cancer in the blood and post-treatment blood cancer in the bone marrow while it was expressed least in normal tissues and cell lines. The Hodgkin lymphoma cell line L428 cell lysate illustrated that there was a high relative protein expression of 6.6 for the CD 86 gene. it indicated that cancer in the esophagus had the highest copy number value and indicated a medium level amplification of the CD 86 gene and prostate cancer had a hemizygous deletion of the CD 86 gene with the least copy number value. Furthermore, on the non-Hodgkin lymphoma cell line REC1, illustrated the highest relative protein expression of the CD 86 gene among the other types of cancer cell line, its protein expression value was 8.19. Also, for cancer type leukemia, the subtype acute myeloid leukemia showed a significant relative protein expression. The acute myeloid leukemia cell line EOL1 indicated that there was a high relative protein expression of 6.5. However, the protein expression for CD 80 is yet to be elucidated.ConclusionsTaken together, CD 80 ad 86 may be potential biomarkers of great clinical significance. The Kaplan Meier plots unveiled that CD 86 and CD 80 were significantly associated with overall survival analysis in the Large B-cell lymphoma, and the different tumor types.

Deregulated miRNAs Contribute to Silencing of B-Cell Specific Transcription Factors and Activation of NF-κB in Classical Hodgkin Lymphoma

A hallmark of classical Hodgkin lymphoma (cHL) is the attenuation of B-cell transcription factors leading to global transcriptional reprogramming. The role of miRNAs (microRNAs) involved in this process is poorly studied. Therefore, we performed global miRNA expression profiling using RNA-seq on commonly used cHL cell lines, non-Hodgkin lymphoma cell lines and sorted normal CD77+ germinal centre B-cells as controls and characterized the cHL miRNome (microRNome). Among the 298 miRNAs expressed in cHL, 56 were significantly overexpressed and 23 downregulated (p < 0.05) compared to the controls. Moreover, we identified five miRNAs (hsa-miR-9-5p, hsa-miR-24-3p, hsa-miR-196a-5p, hsa-miR-21-5p, hsa-miR-155-5p) as especially important in the pathogenesis of this lymphoma. Target genes of the overexpressed miRNAs in cHL were significantly enriched (p < 0.05) in gene ontologies related to transcription factor activity. Therefore, we further focused on selected interactions with the SPI1 and ELF1 transcription factors attenuated in cHL and the NF-ĸB inhibitor TNFAIP3. We confirmed the interactions between hsa-miR-27a-5p:SPI1, hsa-miR-330-3p:ELF-1, hsa-miR-450b-5p:ELF-1 and hsa-miR-23a-3p:TNFAIP3, which suggest that overexpression of these miRNAs contributes to silencing of the respective genes. Moreover, by analyzing microdissected HRS cells, we demonstrated that these miRNAs are also overexpressed in primary tumor cells. Therefore, these miRNAs play a role in silencing the B-cell phenotype in cHL.

Temporal Splicing Switches in Elements of the TNF-Pathway Identified by Computational Analysis of Transcriptome Data for Human Cell Lines

Alternative splicing plays an important role in numerous cellular processes and aberrant splice decisions are associated with cancer. Although some studies point to a regulation of alternative splicing and its effector mechanisms in a time-dependent manner, the extent and consequences of such a regulation remains poorly understood. In the present work, we investigated the time-dependent production of isoforms in two Hodgkin lymphoma cell lines of different progression stages (HD-MY-Z, stage IIIb and L-1236, stage IV) compared to a B lymphoblastoid cell line (LCL-HO) with a focus on tumour necrosis factor (TNF) pathway-related elements. For this, we used newly generated time-course RNA-sequencing data from the mentioned cell lines and applied a computational pipeline to identify genes with isoform-switching behaviour in time. We analysed the temporal profiles of the identified events and evaluated in detail the potential functional implications of alterations in isoform expression for the selected top-switching genes. Our data indicate that elements within the TNF pathway undergo a time-dependent variation in isoform production with a putative impact on cell migration, proliferation and apoptosis. These include the genes TRAF1, TNFRSF12A and NFKB2. Our results point to a role of temporal alternative splicing in isoform production, which may alter the outcome of the TNF pathway and impact on tumorigenesis.

Role of Calcium Signaling in GA101-Induced Cell Death in Malignant Human B Cells

GA101/obinutuzumab is a novel type II anti-CD20 monoclonal antibody (mAb), which is more effective than rituximab (RTX) in preclinical and clinical studies when used in combination with chemotherapy. Ca2+ signaling was shown to play a role in RTX-induced cell death. This report concerns the effect of GA101 on Ca2+ signaling and its involvement in the direct cell death induced by GA101. We reveal that GA101 triggered an intracellular Ca2+ increase by mobilizing intracellular Ca2+ stores and activating Orai1-dependent Ca2+ influx in non-Hodgkin lymphoma cell lines and primary B-Cell Chronic Lymphocytic Leukemia (B-CLL) cells. According to the cell type, Ca2+ was mobilized from two distinct intracellular compartments. In Raji, BL2, and B-CLL cells, GA101 induced a Ca2+ release from lysosomes, leading to the subsequent lysosomal membrane permeabilization and cell death. Inhibition of this calcium signaling reduced GA101-induced cell death in these cells. In SU-DHL-4 cells, GA101 mobilized Ca2+ from the endoplasmic reticulum (ER). Inhibition of ER replenishment, by blocking Orai1-dependent Ca2+ influx, led to an ER stress and unfolded protein response (UPR) which sensitized these cells to GA101-induced cell death. These results revealed the central role of Ca2+ signaling in GA101’s action mechanism, which may contribute to designing new rational drug combinations improving its clinical efficacy.

Hodgkin lymphoma cell lines: to separate the wheat from the chaff

Characteristic components of Hodgkin lymphoma (HL) tissue are the mono- or multinucleated Hodgkin-Reed-Sternberg (HRS) cells. Given the challenges of isolating these rare malignant cells and the difficulty in culturing cells from patients, many investigators have tried to establish cell lines in efforts to develop cellular tools for in vitro studies. A limited number of HL cell lines exist and have provided valuable insights into HL pathobiology. A literature survey indicated that 35 cell lines derived from HL patients have been published. To determine whether all these alleged HL cell lines hold up to scrutiny, we examined the available data and also put some of these cell lines to the test of hierarchical clustering, providing additional information regarding assignment to cell line type and tissue derivation. Hierarchical clustering separated the bona fide (classical) HL cell lines completely from cell lines derived from other lymphoma categories and proved conclusively that HL cell lines represent a distinct entity, irrespective of the cellular origin of the HRS cells. We conclude by pointing out the need for an intensified search for new cell culture avenues in order to develop a new generation of informative HL cell lines covering more widely the spectrum of HL stages and subtypes.