Downregulation of STAT3 in EBV-positive Hodgkin lymphoma
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ABSTRACT:
PROVIDER: PRJNA842009 | ENA |
REPOSITORIES: ENA
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Project description:STAT3 encodes an oncogenic transcription factor which is activated via various signalling pathways or Epstein Barr virus (EBV)-infection. The tumor cells of Hodgkin lymphoma (HL) are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, downregulation of transcription factors mediating B-cell differentiation, and EBV-infection. HL cell lines represent useful models to investigate the molecular pathology and deduced treatment options in this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but nevertheless HLX negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and gene expression profiling data revealed amplified and overexpressed candidates involved in opposed regulation of STAT3 and EBV. Subsequent analyses demonstrated that IRF4 and NFATC inhibited STAT3 expression. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. MIR155 (STAT3 target gene) and BCL11A and SPIB (target genes of HLX) are described as suppressors and activators of EBV and showed reduced and elevated expression levels in AM-HLH, respectively. Taken together, this cell line deals with two conflicting oncogenic drivers, namely JAK2-STAT3-signalling and EBV-infection but is sensitive to cytokine signalling, mediating a switch between these aberrant pathways. Thus, AM-HLH represents an interesting cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.
2022-12-31 | GSE204717 | GEO
Project description:Epstein–Barr virus-positive (EBV+) diffuse large B-cell lymphoma (DLBCL) and EBV+ classic Hodgkin lymphoma (CHL) are major B-cell lymphomas with EBV infection in elderly patients. Although they are regarded as distinct clinicopathologic entities, distinguishing EBV+ CHL from EBV+ DLBCL is often challenging because of their overlapping histological and immunophenotypic features. We characterized the spectrum of EBV+ large B-cell lymphoma in 57 patients aged ≥50 years, including 35 EBV+ DLBCL (12 polymorphic DLBCL [pDLBCL] and 23 monomorphic DLBCL [mDLBCL]) and 22 EBV+ CHL. Gene expression profiling revealed interferon-γ (IFNγ)-enrichment with overexpression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme, in more than half of pDLBCL (5/8), but less in mDLBCL (3/19) and CHL (1/19). Fluorescence in situ hybridization showed a higher frequency of 9p24.1-altered cells in CHL (54%; interquartile range [IQR], 42%–89%), but lower in pDLBCL (18%; IQR, 12%–23%) and mDLBCL (5%; IQR, 0%–30%). Notably, immunohistochemical expression of PDL1 was higher in pDLBCL than in mDLBCL, suggesting IFNγ-mediated upregulation. DLBCL with EBV latency type III (n = 13) exhibited lower tumor PDL1 expression and reduced IDO1-enriched microenvironment. Multivariate analysis of the total cohort revealed that both EBV latency type III and Eastern Cooperative Oncology Group performance status ≥2 were independently associated with shorter overall survival. EBV+ large B-cell lymphoma spectrum was reclassified into four molecular groups: (1) EBV latency type III suggestive of immune senescence (n = 10, 22%), (2) high proportion of 9p24.1-alteration (n = 9, 20%); (3) high IFNγ signature score (n = 9, 20%), and (4) low IFNγ signature score (n = 18, 39%). Moreover, these groups were identified using surrogate immunohistochemical markers: EBNA2, PDL1, and IDO1. In conclusion, the molecular studies assessing tumor–host interaction enhances understanding of the EBV+ large B-cell lymphoma spectrum and benefits pathological diagnosis and clinical management.
2025-12-11 | GSE305165 | GEO
Project description:Redefining the Spectrum of EBV-Positive Diffuse Large B-Cell Lymphoma and EBV-Positive Classic Hodgkin Lymphoma
| PRJNA1304530 | ENA
Project description:STAT3 is a transcription factor which is activated via various signaling transduction pathways or Epstein-Barr virus (EBV) infection and plays an oncogenic role in lymphoid malignancies including Hodgkin lymphoma (HL). The tumor cells of HL are derived from germinal center B-cells and transformed by chromosomal rearrangements, aberrant signal transduction, deregulation of developmental transcription factors, and EBV activity. HL cell lines represent useful models to investigate molecular principles and deduced treatment options of this malignancy. Using cell line L-540, we have recently shown that constitutively activated STAT3 drives aberrant expression of hematopoietic NKL homeobox gene HLX. Here, we analyzed HL cell line AM-HLH which is EBV-positive but, nevertheless, HLX-negative. Consistently, AM-HLH expressed decreased levels of STAT3 proteins which were additionally inactivated and located in the cytoplasm. Combined genomic and expression profiling data revealed several amplified and overexpressed gene candidates involved in opposed regulation of STAT3 and EBV. Corresponding knockdown studies demonstrated that IRF4 and NFATC2 inhibited STAT3 expression. MIR155 (activated by STAT3) and SPIB (repressed by HLX) showed reduced and elevated expression levels in AM-HLH, respectively. However, treatment with IL6 or IL27 activated STAT3, elevated expression of HLX and MIR155, and inhibited IRF4. Taken together, this cell line deals with two conflicting oncogenic drivers, namely, JAK2-STAT3 signaling and EBV infection, but is sensitive to switch after cytokine stimulation. Thus, AM-HLH represents a unique cell line model to study the pathogenic roles of STAT3 and EBV and their therapeutic implications in HL.
| S-EPMC9313380 | biostudies-literature
Project description:To investigate the biological differences between EBV-/HIV-, EBV+/HIV- and EBV+/HIV+ classic Hodgkin lymphoma, we performed RNA sequencing of 19 pre-treatment formalin-fixed paraffin-embedded (FFPE) whole lymph node biopsies of cHL.
2025-02-19 | GSE289903 | GEO
Project description:Epstein-Barr virus (EBV)- encoded RNAs (EBERs) are aboundance in all EBV lantency, it was found that EBERs may contribute to the oncogenesis. To study the role of EBV-encoded small RNAs (EBERs) in Hodgkin lymphoma, we transfected Hodgkin lymphoma cell lines, KMH2 and L428, with EBER1 and screen with microarrays to verify what is the possible role of the EBER1 in Hodgkin lymphoma.
2010-02-13 | GSE12427 | GEO
Project description:Nasal T/NK lymphoma is a unique subtype of non-Hodgkin lymphoma (NHL) that is aggressive and incurable closely associated with Epstein-Barr virus (EBV)3. The clonal expansion of EB infected T- or NK cell is also seen in patients with chronic active EBV (CAEBV) infection, suggesting that two diseases might partly share a similar mechanism by which EBV affect host cellular genes. In order to understand the pathogenesis of EBV-associated T/NK lymphoproliferative disorders (LPD) and design new therapies, we employed a novel EBV DNA microarray to compare patterns of EBV expression in SNK/T cells established from EBV-associated T/NK LPD. Keywords: parallel sample
2005-09-20 | GSE2414 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE25986: Gene expression profiling of cell lines derived from classical Hodgkin lymphoma GSE25987: Gene expression profiling of Hodgkin lymphoma cell line KMH2: Comparison of CIITA-BX648577 knockdown cultures with non-silencing controls GSE25989: Copy number analysis of Hodgkin lymphoma cell lines KM-H2 and L-428 Refer to individual Series *** This submission represents the microarray gene expression and microarray copy number components of the study
2010-12-11 | E-GEOD-25990 | biostudies-arrayexpress
Project description:Epstein Barr Virus (EBV) has been recognized for its ability to transform B lymphocytes and for its association with different types of cancers including Hodgkin lymphoma. In addition, EBV may also modulate the microenvironment of HL. In this study, we aimed to investigate the prevalence of EBV among HL cases in Ethiopia and to assess the tissue cellular composition of EBV-related and EBV-unrelated cases. We constructed a tissue microarray (TMA) of 126 consecutive cases of classical HL (CHL) and nodular lymphocyte predominant HL (NLPHL) from a tertiary cancer centre, Tikur Anbessa Hospital, Addis Ababa, Ethiopia, and evaluated a panel of immunohistochemical markers. The quantification of immune cells was performed using HALO 2.3, a platform for image analysis from Indica Lab Inc. A total of 77/126 (61.1%) of HL cases expressed LMP1/EBER. Infiltration of CD8+, T-bet+ and FoxP3+ cells was higher in the microenvironment of EBV-related CHL, with P values of <0.001, <0.001 and <0.016, respectively. In contrast, the expression of PD1 was higher in the microenvironment of EBV-unrelated CHL cases (P < 0.001). Unlike in Western countries, the majority of HL cases in Ethiopia were associated with EBV. As FoxP3+ and PD1-expressing cells are thought to participate in down regulation of the immune response by different mechanisms, this finding highlights the previously unrecognized possibility that distinct immunosuppressive mechanisms may be ongoing within EBV positive and negative HL types. This may have important prognostic and therapeutic implications.
| S-EPMC10861371 | biostudies-literature
Project description:Global proteomics profiling of anaplastic large cell lymphoma cell lines DEL, SU-DHL-1 (ALK+), Mac-1, Mac-2A (ALK-) as well as Hodgkin lymphoma cell lines L-428, L-540, L-1236 and HDLM-2.
2022-08-12 | PXD031907 | Pride