Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma

Blood ◽  
2002 ◽  
Vol 99 (2) ◽  
pp. 618-626 ◽  
Author(s):  
Brian F. Skinnider ◽  
Andrew J. Elia ◽  
Randy D. Gascoyne ◽  
Bruce Patterson ◽  
Lorenz Trumper ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Clinicopathologic Features ◽  
Stat Proteins ◽  
Tissue Sections ◽  
Non Hodgkin Lymphoma ◽  
Constitutive Phosphorylation

Abstract The unique clinicopathologic features of Hodgkin lymphoma (HL) are due to the multiple cytokines produced by its neoplastic cells, the Hodgkin and Reed-Sternberg (HRS) cells. Cytokine signaling is mediated through the signal transducer and activator of transcription (STAT) family of transcription factors. Immunoblotting and immunohistochemistry were used to examine cell lines and tissue sections derived from patients with HL and non-Hodgkin lymphoma (NHL) for expression of activated STAT proteins. Constitutive phosphorylation of STAT6 and STAT3 was common in HL. STAT6 was constitutively phosphorylated in 5 of 5 HL cell lines and in HRS cells from 25 of 32 (78%) classical HL cases. STAT3 was constitutively phosphorylated in 4 of 5 HL cell lines and in HRS cells from 27 of 31 (87%) classical HL cases. Only 4 of 24 NHL cases demonstrated constitutive STAT6 activation, whereas STAT3 activation was observed in 6 of 13 (46%) cases of B-cell NHL and 8 of 11 (73%) cases of T-cell NHL. Constitutive STAT5 phosphorylation was not a common feature of HL or NHL. STAT6 mediates signaling by interleukin 13 (IL-13), a cytokine frequently expressed by HRS cells. Antibody-mediated neutralization of IL-13 resulted in significant decreases in both cellular proliferation and levels of phosphorylated STAT6 of HL cell lines. In conclusion, constitutive STAT6 phosphorylation is a common and distinctive feature of HRS cells in classical HL, whereas STAT3 activation was regularly present in both HL and NHL. These results suggest that IL-13 signaling is largely responsible for the constitutive STAT6 activation observed in HRS cells and further implicate IL-13 as an important growth factor in classical HL.

scholarly journals Epigenetic Regulation of miR-92a and TET2 and Their Association in Non-Hodgkin Lymphoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Esther K. Elliott ◽  
Lloyd N. Hopkins ◽  
Robert Hensen ◽  
Heidi G. Sutherland ◽  
Larisa M. Haupt ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Genes ◽  
Cpg Islands ◽  
Mature Mirnas ◽  
Tumour Suppressor Genes ◽  
Promoter Regions ◽  
Aberrant Expression ◽  
Non Hodgkin Lymphoma

MicroRNAs (miRNAs) are well known for their ability to regulate the expression of specific target genes through degradation or inhibition of translation of the target mRNA. In various cancers, miRNAs regulate gene expression by altering the epigenetic status of candidate genes that are implicated in various difficult to treat haematological malignancies such as non-Hodgkin lymphoma by acting as either oncogenes or tumour suppressor genes. Cellular and circulating miRNA biomarkers could also be directly utilised as disease markers for diagnosis and monitoring of non-Hodgkin lymphoma (NHL); however, the role of DNA methylation in miRNA expression regulation in NHL requires further scientific inquiry. In this study, we investigated the methylation levels of CpGs in CpG islands spanning the promoter regions of the miR-17–92 cluster host gene and the TET2 gene and correlated them with the expression levels of TET2 mRNA and miR-92a-3p and miR-92a-5p mature miRNAs in NHL cell lines, tumour samples, and the whole blood gDNA of an NHL case control cohort. Increased expression of both miR-92a-3p and miR-92a-5p and aberrant expression of TET2 was observed in NHL cell lines and tumour tissues, as well as disparate levels of dysfunctional promoter CGI methylation. Both miR-92a and TET2 may play a concerted role in NHL malignancy and disease pathogenesis.

PERILOUS HIV BRINGS OUT DEADLY CANCERS

2020 ◽  
pp. 1-5
Author(s):  
Camila A Carlman ◽  
Bharat Mishra ◽  
Anita Patel
Keyword(s):  
Immune System ◽  
Hodgkin Lymphoma ◽  
Cancer Progression ◽  
Kaposi's Sarcoma ◽  
Cellular Proliferation ◽  
Kaposi’S Sarcoma ◽  
Hiv Patients ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk ◽  
Risk Of Cancer

Human Immunodeficiency Virus (HIV) infection is both infectious and contagious disease. The people infected with HIV have an increased risk of cancer while comparing with uninfected people. Kaposi’s sarcoma, aggressive B-cell Non-Hodgkin Lymphoma & cervical cancer are the three types of cancers which are termed as “HIV –associated cancers”. Apart from these cancers, HIV patients are prone to cancers of anus, liver, lung, pharynx which are termed as “non-AIDS defining cancers”. Viral oncogenesis and cytokine induced growth contribute to the development of Kaposi sarcoma. Several virally encoded genes such as bcl-2, IL-6, cyclin-D, GPCR & interferon regulatory factor, plays key role in cellular proliferation and survival.  Infection with HIV weakens the immune system and reduces the body’s ability to fight against viral infections that may lead to cancer. Immunosuppression and inflammation in HIV patients also contribute to cancer progression. The complications of AIDS- related cancers include easy bleeding and bruising, tiredness, nausea, vomiting, poor appetite, mouth sores, hair loss etc. According to the data, HIV infected males are more susceptible to Kaposi’s sarcoma and Non- Hodgkin Lymphoma whereas females are more liable to cervical cancers. Early diagnosis and treatment options help to drop the risk of AIDS related cancers. The HAART therapy reduces the risk of cancer in HIV patients by lowering the amount of HIV circulating in blood, so that function of immune system to fight against the virus can be restored. Other treatment methods are chemotherapy, immunotherapy, radiation and surgery.

Mutations of the Tumor Suppressor Gene SOCS-1 in Classical Hodgkin Lymphoma Are Frequent and Associated with Nuclear Phospho-STAT5 Accumulation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 19-19 ◽  
Author(s):  
Marc A. Weniger ◽  
Ingo Melzner ◽  
Christiane K. Menz ◽  
Silke Wegener ◽  
Alexandra J. Bucur ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Suppressor Gene ◽  
Cell Lines ◽  
B Cell Lymphoma ◽  
Suppressor Gene ◽  
Cytokine Signaling ◽  
Sequencing Analysis ◽  
Classical Hodgkin Lymphoma

Abstract The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P (BLOOD, 105, 2535–42, 2005). For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (p<0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.

Targeting the Human Double Minute (HDM)-2 p53 Ubiquitin Ligase as a Strategy Against Non-Hodgkin Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1374-1374
Author(s):  
Richard J. Jones ◽  
Dajun Yang ◽  
Nathalie Bruey-Sedano ◽  
Robert Z. Orlowski
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Human Umbilical Cord ◽  
Wild Type ◽  
Inhibition Of Proliferation ◽  
P53 Expression ◽  
Non Hodgkin Lymphoma ◽  
Drug Concentrations ◽  
Chemotherapy Agents ◽  
The Impact

Abstract Background: The ubiquitin-proteasome pathway has been validated as a target for non-Hodgkin lymphoma (NHL) with the recent approval of bortezomib for mantle cell lymphoma (MCL). In addition to anti-tumor activity, however, proteasome inhibitors have pleiotropic effects, including activation of an anti-apoptotic heat shock protein response, and their use clinically is complicated by toxicities such as peripheral neuropathy. By targeting E3 ubiquitin ligases, which are involved in ubiquitination of only a small subset of cellular proteins, it may be possible to achieve more specific anti-tumor effects with a better therapeutic index. One such attractive target is HDM-2, which is responsible for ubiquitination of the p53 tumor suppressor. Methods: To evaluate the therapeutic potential of agents targeting HDM-2, we studied the impact of the small molecule MI-63, an inhibitor of the HDM-2-p53 interaction, in both p53 wild-type and -mutant cell line models. Results: Treatment of wild-type p53 MCL, NHL, and acute lymphocytic leukemia (ALL) cell lines with MI-63 induced a dose- and time-dependent inhibition of proliferation, with an IC50 in the 1.0–5.0 μM range. This was associated with G1/S cell cycle arrest, and apoptosis mediated by caspases-3, 8 and 9. MI-63 induced accumulation and phosphorylation of p53 at serine 15 and 37, and also enhanced HDM-2 levels. Multiple p53 target genes were induced, including p21Cip1 and p53-upregulated modulator of apoptosis (PUMA), resulting in cleavage of poly-ADP-ribose-polymerase (PARP). MI-63 also decreased the levels of the ribonucleotide reductase subunit R2, and caused a corresponding increase in the R2p53 subunit. MI-63 also decreased the levels of E2F. Cell lines expressing certain p53 mutants were sensitive to the effects of MI-63, resulting in apoptosis. Cells without p53 expression were less sensitive to MI-63, but at higher drug concentrations proliferation was still inhibited, indicating a possible impact on HDM-2-mediated but p53-independent cell death pathways. Primary human umbilical cord vein endothelial cell growth was also inhibited and cells failed to recover after extended exposure to MI-63, whereas primary PBMC’s were unaffected by MI-63. Combinations of MI-63 with the molecularly targeted chemotherapy agents bortezomib and rapamycin were synergistic, with mean CI values of 0.88 and 0.6 respectively. The conventional chemotherapy agents doxorubicin and cisplatin were less effective at inducing synergism, with mean CI values of 1.06 and 0.9 respectively. Pretreatment of cells with MI-63 followed by chemotherapy was antagonistic with all agents used, while treatment with a chemotherapeutic first followed by MI-63 was additive to synergistic, indicating a sequence-dependent interaction. Conclusions: Inhibition of the HDM-2-p53 interaction is a promising approach both by itself, and in combination with currently used chemotherapeutics, against lymphoid malignancies, providing a rationale for translation of such agents into the clinic.

Clinicopathologic features and treatment outcome of primary intestinal non-Hodgkin lymphoma: A single center experience.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19523-e19523
Author(s):  
Wei-Hsun Hsu ◽  
Kun-Huei Yeh ◽  
Chung-Wu Lin ◽  
Chih-Hung Hsu ◽  
Ann-Lii Cheng ◽  
...  
Keyword(s):  
Small Intestine ◽  
Treatment Outcome ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
B Cell Lymphoma ◽  
Clinicopathologic Features ◽  
Non Hodgkin Lymphoma

e19523 Background: Primary intestinal non-Hodgkin lymphoma (NHL) is a rare but heterogeneous disease in East Asia. However, the benefit of multidisciplinary treatment is still in debate. We characterized the clinicopathologic features, and treatment outcome in a single institute database. Methods: Patients with NHL primarily involving the intestine and treated during 1992 to 2008 were selected from the Cancer Registry of National Taiwan University Hospital. The medical charts and pathology records were carefully reviewed. Results: There were 64 men and 17 women with a median age of 51.5 years. Sites involved were colon/rectum (53.2%), small intestine (30.9%), and duodenum (13%). Histopathology subclassification included diffuse large B-cell lymphoma (DLBCL) (61.7%), mucosa-associated lymphoid tissue lymphoma (11.1%), Burkitt’s lymphoma (8.6%), T cell lymphoma (6.2%), follicular lymphoma (2.5%), mantle cell lymphoma (1.2 %) and others (8.6%). Ann Arbor stage IE to IIE accounted for 61.7%, whereas lower IPI score (1-2) were 54.8%. Among them, 27 patients received surgery plus chemotherapy, 60 received chemotherapy, and 4 had radiotherapy. At average follow-up of 48.7 months, 5 year survival rate were 59%, 43% and 51% for colon/rectum, small intestine, and duodenal NHL, respectively (p=0.45). Surgery plus chemotherapy versus chemotherapy alone showed no survival benefit in lower IPI group (p=0.682) nor in higher IPI (3-5) group (p=0.939). A trend of better median overall survival (mOS) was seen in rituximab group than in non-rituximab group in DLBCL subtypes (not reach vs. 39.8mo, p=0.075). In univariate analysis, stage III/IV (p=0.008), IPI score greater than 2 (p=0.011), and T cell histology (p<0.001) were significant prognostic factors for poor OS. In multivariate analysis, T cell histology remained the independent prognostic factor for inferior OS (p<0.001, HR: 20.3, 95% CI: 5.1-80.4). Conclusions: Although B cell NHL was the majority of primary intestinal NHL in our institute, T cell histology has significant inferior survival. Chemotherapy is still the backbone of treatment for primary intestinal NHL. The benefit of rituximab to intestinal DLBCL needs further confirmation.

Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival

2006 ◽  
Vol 18 (4) ◽  
pp. 449-455 ◽  
Author(s):  
Olivia Cochet ◽  
Catherine Frelin ◽  
Jean-François Peyron ◽  
Véronique Imbert
Keyword(s):  
Cell Survival ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Stat Proteins ◽  
Constitutive Activation

scholarly journals SLAMF7 in Primary Effusion Lymphoma, Target for Individualized Therapy?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5300-5300
Author(s):  
Hilmar Quentmeier ◽  
Claudia Pommerenke ◽  
Wilhelm G Dirks ◽  
Vivien Hauer ◽  
Max Koeppel ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Conflicts Of Interest ◽  
Primary Effusion Lymphoma ◽  
B Cell Lymphoma ◽  
B Cell Differentiation ◽  
Expression Array ◽  
Non Hodgkin Lymphoma ◽  
Novel Therapeutic Strategies

Abstract Primary effusion lymphoma (PEL) is a rare, aggressive form of B-cell lymphoma. With a median survival time of around six months the prognosis for PEL patients is poor. Therefore, there is a medical need for novel therapeutic strategies. We performed expression array analysis to find potential targets for antibody-based therapy. Unsupervised clustering analysis revealed that PEL cell lines grouped separate from cell lines derived from other B-non Hodgkin lymphoma (B-NHL) entities. Notably, PEL and Hodgkin Lymphoma (HL) cell lines clustered on one arm, separate from all cell lines representing less-differentiated B-NHL variants. PEL and HL cell lines were characterized by a set of common up- and downregulated genes. Typical for PEL and HL was the expression of CCND2 and the absence of Brutons tyrosine kinase and of B-cell markers including CD19, CD20, CD79A and CD79B. Highly expressed in PEL - but not in HL - were CD138, IL-10, SLAMF7 and PRDM1. PRDM1/BLIMP1 is a master regulator of terminal B-cell differentiation. Originally described as repressor, BLIMP1 can also enhance transcription of SLAMF7 in multiple myeloma (MM) and of IL-10 in type 1 regulatory T-cells. Thus, coexpression of the three genes suggests a causal relationship between transcriptionally active PRDM1/BLIMP1 and its targets SLAMF7 and IL-10 also in PEL. Expression of SLAMF7 in PEL is especially noteworthy because a monoclonal antibody targeting SLAMF7 (elotuzumab) has been approved for treatment of patients with MM. We observed that SLAMF7 is comparably expressed in PEL and in MM cell lines. If the results on cell lines can be translated to primary PEL, i.e. if PEL tumor cells express SLAMF7, the patients might benefit from an antibody-based targeted therapy against this antigen. Disclosures No relevant conflicts of interest to declare.

scholarly journals Th17/Treg imbalance in COPD development: suppressors of cytokine signaling and signal transducers and activators of transcription proteins

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Larissa E. F. Silva ◽  
Juliana D. Lourenço ◽  
Kaique R. Silva ◽  
Fernanda Paula R. Santana ◽  
Júlia B. Kohler ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Cytokine Signaling ◽  
Chronic Obstructive ◽  
Signal Transducer ◽  
Therapeutic Approaches ◽  
Suppressor Of Cytokine Signaling ◽  
Obstructive Pulmonary Disease ◽  
Signal Transducers ◽  
Stat Proteins ◽  
Suppressors Of Cytokine Signaling

Abstract Th17/Treg imbalance contributes to chronic obstructive pulmonary disease (COPD) development and progression. However, intracellular signaling by suppressor of cytokine signaling (SOCS) 1 and SOCS3 and the proteins signal transducer and activator of transcription (STAT) 3 and STAT5 that orchestrate these imbalances are currently poorly understood. Thus, these proteins were investigated in C57BL/6 mice after exposure to cigarette smoke (CS) for 3 and 6 months. The expression of interleukin was measured by ELISA and the density of positive cells in peribronchovascular areas was quantified by immunohistochemistry. We showed that exposure to CS in the 3rd month first induced decreases in the numbers of STAT5+ and pSTAT5+ cells and the expression levels of TGF-β and IL-10. The increases in the numbers of STAT3+ and pSTAT3+ cells and IL-17 expression occurred later (6th month). These findings corroborate the increases in the number of SOCS1+ cells in both the 3rd and 6th months, with concomitant decreases in SOCS3+ cells at the same time points. Our results demonstrated that beginning with the initiation of COPD development, there was a downregulation of the anti-inflammatory response mediated by SOCS and STAT proteins. These results highlight the importance of intracellular signaling in Th17/Treg imbalance and the identification of possible targets for future therapeutic approaches.

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