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Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival.

ABSTRACT: We have analyzed the role of the REL family members in Hodgkin lymphoma (HL). shRNA targeting of each REL member showed that HL was uniquely dependent on relB, in contrast to several other B-cell lymphomas. In addition, relA and c-rel shRNA expression also decreased HL cell viability. In exploring relB activation further, we found stable NF-?B inducing kinase (NIK) protein in several HL cell lines and that NIK shRNA also affected HL cell line viability. More importantly, 49 of 50 HL patient biopsies showed stable NIK protein, indicating that NIK and the noncanonical pathway are very prevalent in HL. Lastly, we have used a NIK inhibitor that reduced HL but not other B-cell lymphoma cell viability. These data show that HL is uniquely dependent on relB and that the noncanonical pathway can be a therapeutic target for HL. Furthermore, these results show that multiple REL family members participate in the maintenance of a HL phenotype.

SUBMITTER: Ranuncolo SM

PROVIDER: S-EPMC3488888 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Hodgkin lymphoma requires stabilized NIK and constitutive RelB expression for survival.

Ranuncolo Stella M SM Pittaluga Stefania S Evbuomwan Moses O MO Jaffe Elaine S ES Lewis Brian A BA

Blood 20120911 18

We have analyzed the role of the REL family members in Hodgkin lymphoma (HL). shRNA targeting of each REL member showed that HL was uniquely dependent on relB, in contrast to several other B-cell lymphomas. In addition, relA and c-rel shRNA expression also decreased HL cell viability. In exploring relB activation further, we found stable NF-κB inducing kinase (NIK) protein in several HL cell lines and that NIK shRNA also affected HL cell line viability. More importantly, 49 of 50 HL patient biop ...[more]

PMID: 22968463

Similar Datasets

RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation.

Project description:NF-kappaB inducing kinase (NIK) is required for osteoclastogenesis in response to pathologic stimuli, and its loss leads to functional blockade of both alternative and classical NF-kappaB caused by cytoplasmic retention by p100. We now show that deletion of p100 restores the capacity of NIK-deficient osteoclast (OC) precursors to differentiate and normalizes RelB and p65 signaling. Differentiation of NIK-/- precursors is also restored by overexpression of RelB, but not p65. Additionally, RelB-/- precursors fail to form OCs in culture, and this defect is rescued by re-expression of RelB, but not by overexpression of p65. To further support the role of RelB in OCs, we challenged RelB-/- mice with TNF-alpha in vivo and found a diminished osteoclastogenic response. We then examined tumor-induced osteolysis in both RelB-/- and NIK-/- mice by using the B16 melanoma model. Growth of tumor cells in the bone marrow was similar to WT controls, but the absence of either RelB or NIK completely blocked the tumor-induced loss of trabecular bone. Thus, the alternative NF-kappaB pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.

| S-EPMC2268780 | biostudies-literature

Hodgkin lymphoma.

Project description:Hodgkin lymphoma (HL), a B cell-derived cancer, is one of the most common lymphomas. In HL, the tumor cells--Hodgkin and Reed-Sternberg (HRS) cells--are usually very rare in the tissue. Although HRS cells are derived from mature B cells, they have largely lost their B cell phenotype and show a very unusual co-expression of markers of various hematopoietic cell types. HRS cells show deregulated activation of multiple signaling pathways and transcription factors. The activation of these pathways and factors is partly mediated through interactions of HRS cells with various other types of cells in the microenvironment, but also through genetic lesions. The transforming events involved in the pathogenesis of HL are only partly understood, but mutations affecting the NF-?B and JAK/STAT pathways are frequent. The dependency of HRS cells on microenvironmental interactions and deregulated signaling pathways may offer novel strategies for targeted therapies.

| S-EPMC3534167 | biostudies-other

Checkpoint CD47 expression in classical Hodgkin lymphoma.

Project description:The glycoprotein CD47 regulates antiphagocytic activity via signal regulatory protein alpha (SIRPa). This study investigated CD47 expression on Hodgkin and Reed-Sternberg (HRS) cells in the classical Hodgkin lymphoma (cHL) tumour microenvironment and its correlation with prognosis, programmed-death (PD) immune markers, and SIRPa+ leukocytes. We conducted immunohistochemistry with CD47 and SIRPa antibodies on diagnostic biopsies (tissue microarrays) from cHL patients from two cohorts (n = 178). In cohort I (n = 136) patients with high expression of CD47 on HRS cells (n = 48) had a significantly inferior event-free survival [hazard ratio (HR) = 5.57; 95% confidence interval (CI), 2.78-11.20; p < 0.001] and overall survival (OS) (HR = 8.54; 95% CI, 3.19-22.90; p < 0.001) compared with patients with low expression (n = 88). The survival results remained statistically significant in multivariable Cox regression adjusted for known prognostic factors. In cohort II (n = 42) high HRS cell CD47 expression also carried shorter event-free survival (EFS) (HR = 5.96; 95% CI, 1.20-29.59; p = 0.029) and OS (HR = 5.61; 95% CI, 0.58-54.15; p = 0.136), although it did not retain statistical significance in the multivariable analysis. Further, high CD47 expression did not correlate with SIRPa+ leukocytes or PD-1, PD-L1 and PD-L2 expression. This study provides a deeper understanding of the role of CD47 in cHL during an era of emerging CD47 therapies.

| S-EPMC9310712 | biostudies-literature

Polymorphisms in immune function genes and non-Hodgkin lymphoma survival.

Project description:IntroductionCytokines play a critical role in regulating the immune system. In the tumor microenvironment, they influence survival, proliferation, differentiation, and movement of both tumor and stromal cells, and regulate tumor interactions with the extracellular matrix. Given these biologic properties, there is reason to hypothesize that cytokine activity influences the pathogenesis of non-Hodgkin lymphoma (NHL).MethodsWe investigated the effect of genetic variation in cytokine genes on NHL prognosis and survival by evaluating genetic variation in individual SNPs as well as the combined effect of multiple deleterious genotypes. Survival information from 496 female incident NHL cases diagnosed during 1996-2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008. Survival analyses were conducted by comparing Kaplan-Meier curves and hazard ratios (HR) were computed using Cox proportional hazard models adjusting for demographic and tumor characteristics for genes that were suggested by previous studies to be associated with NHL survival.ResultsWe found that the variant IL6 genotype is significantly associated (HR = 0.42; 95%CI: 0.23-0.77) with a decreased risk of death, as well as relapse and secondary cancer occurrence, among those with NHL. We also found that risk of death, relapse, and secondary cancers varied by specific SNPs for the follicular, DLBCL, and CLL/SLL histologic types. We identified combinations of polymorphisms whose combined deleterious effect significantly alter overall NHL survival and disease-free survival.ConclusionOur study provides evidence that the identification of genetic polymorphisms in cytokine genes may help improve the prediction of NHL survival and prognosis.

| S-EPMC3326600 | biostudies-literature

Adult nodular lymphocyte-predominant Hodgkin lymphoma: treatment modality utilization and survival.

Project description:Early-stage nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is associated with a favorable prognosis. Our aim was to evaluate the patterns of care of radiotherapy utilization in this disease and to define the relationship between treatment modality and survival. The National Cancer Database was queried for patients with stages I-II NLPHL diagnosed from 2004 to 2012. Patients were compared based on primary therapy into four categories: radiotherapy, chemotherapy, both, or neither. Covariate-adjusted and propensity score-weighted (PS) Cox proportional hazards models were used, adjusting for potential factors confounding survival. After exclusions, 1420 patients were evaluated, 571 (40%) received radiotherapy alone, 318 (22%) received chemotherapy alone, 351 (25%) received both, and 180 (13%) received neither. Younger patient age (P = 0.001), female gender (P = 0.019), and chemotherapy use (P < 0.001) were associated with decreased radiotherapy utilization. On PS, radiation alone (HR = 0.298, P < 0.001) and chemoradiotherapy (HR = 0.258, P < 0.001) were associated with improved survival compared to no upfront therapy, but the use of chemotherapy alone did not statistically differ compared to no initial therapy (HR = 0.784, P = 0.078). In this large database analysis, over one-third of patients with early-stage NLPHL did not receive radiotherapy as a component of initial therapy. The omission of upfront radiotherapy was associated with inferior survival.

| S-EPMC5911587 | biostudies-other

Hodgkin lymphoma-educated macrophages

Project description:Comparative proteome analysis of HL and DLBCL educated human macrophages by SWATH-MS.

2020-01-29 | PXD016128 | Pride

CD163 expression was associated with angiogenesis and shortened survival in patients with uniformly treated classical Hodgkin lymphoma.

Project description:BackgroundRecent studies have reported the prognostic value of tissue-associated magrophages (TAMs) in classical Hodgkin lymphoma (cHL). In addition, TAMs are implicated in the tumor angiogenesis. In this study, we examined the prognostic relevance of TAMs in relation to vascular endothelial growth factor (VEGF) expression and angiogenesis in uniformly treated cases of cHL.MethodsDiagnostic tissue from 116 patients with ABVD-treated cHL was evaluated retrospectively by immunohistochemical analysis for CD68, CD163 and VEGF expression and for CD31 expression as a measure of microvessel density (MVD).ResultsHigh CD163 expression (? 35% of cellularity) correlated with VEGF expression (Pearson's Chi-square test, P = 0.008) and MVD (Spearman correlation coefficient 0.310, P<0.001). High CD163 expression was associated with inferior event-free survival (EFS, P = 0.005) and overall survival (OS, P<0.001) in univariate analysis. In multivariate analysis, high CD163 expression was strongly associated with inferior EFS (P = 0.043) and OS (P = 0.008). Patients with high MVD had a lower OS than those with low MVD, but the difference was not significant (P = 0.071, respectively). While high expression of CD68 was also associated with inferior EFS (P = 0.007), it showed no correlation with VEGF or MVD.ConclusionsOur data confirms that CD163 expression provides independent prognostic information in cHL. The correlation of CD163 with VEGF expression and MVD suggests the role of CD163-positive cells in tumor angiogenesis of cHL.

| S-EPMC3906082 | biostudies-literature

Pre-diagnosis cigarette smoking and overall survival in non-Hodgkin lymphoma.

Project description:We examined whether smoking prior to non-Hodgkin lymphoma (NHL) diagnosis was associated with overall survival (OS) and conducted a meta-analysis to assess the evidence relating pre-diagnosis cigarette smoking with OS. Among 523 NHL patients, worse OS was suggested for greater pre-diagnostic smoking habits when compared to never smokers. In the meta-analysis (n = 5 patient populations), inferior OS was observed for greater number of cigarettes smoked per day, years of cigarette smoking, and pack-years of cigarette smoking. The inferior survival was more pronounced for follicular than for diffuse large B cell lymphoma. Pre-diagnosis cigarette smoking may adversely impact the survival of NHL patients.

| S-EPMC3797194 | biostudies-literature

Genetic polymorphisms in the metabolic pathway and non-Hodgkin lymphoma survival.

Project description:Metabolic pathway enzymes, such as Cytochrome P450 (CYP), glutathione S-transferase (GST), and N-acetyltransferases (NAT) are involved in activation and detoxification of environmental carcinogens as well as drug metabolism. We hypothesized that the genetic variations in such metabolic pathways may affect NHL prognosis and survival. Follow-up information of 496 female NHL incident cases diagnosed during 1996-2000 in Connecticut were abstracted from the Connecticut Tumor Registry in 2008; survival analyses were conducted by comparing the Kaplan-Meier curves, and hazard ratios (HR) were computed from the Cox Proportional Hazard models adjusting for demographic and tumor characteristics which were suggested by previous studies to be determinants of NHL survival. We identified six SNPs from four metabolism genes (CYP2E1, GSTP1, GSTT1, and NAT1) that were associated with NHL survival. Specifically, polymorphisms in GSTT1 were associated with follicular lymphoma survival; and polymorphisms in CYP2E1, GSTP1, and NAT1 were associated with survival of chronic lymphocytic leukemia/small lymphocytic lymphoma. Our study suggests that genetic polymorphisms in metabolic pathways may help improve the prediction of NHL survival and prognosis.

| S-EPMC2964927 | biostudies-literature

Aberrant expression of homeobox gene SIX1 in Hodgkin lymphoma.

Project description:In Hodgkin lymphoma (HL) we recently identified deregulated expression of homeobox genes MSX1 and OTX2 which are physiologically involved in development of the embryonal neural plate border region. Here, we examined in HL homeobox gene SIX1 an additional regulator of this embryonal region mediating differentiation of placodal precursors. SIX1 was aberrantly activated in 12 % of HL patient samples in silico, indicating a pathological role in a subset of this B-cell malignancy. In addition, SIX1 expression was detected in HL cell lines which were used as models to reveal upstream factors and target genes of this basic developmental regulator. We detected increased copy numbers of the SIX1 locus at chromosome 14q23 correlating with enhanced expression while chromosomal translocations were absent. Moreover, comparative expression profiling data and pertinent gene modulation experiments indicated that the WNT-signalling pathway and transcription factor MEF2C regulate SIX1 expression. Genes encoding the transcription factors GATA2, GATA3, MSX1 and SPIB - all basic lymphoid regulators - were identified as targets of SIX1 in HL. In addition, cofactors EYA1 and TLE4, respectively, contrastingly mediated activation and suppression of SIX1 target gene expression. Thus, the protein domain interfaces may represent therapeutic targets in SIX1-positive HL subsets. Collectively, our data reveal a gene regulatory network with SIX1 centrally deregulating lymphoid differentiation and support concordance of lymphopoiesis/lymphomagenesis and developmental processes in the neural plate border region.

| S-EPMC4741883 | biostudies-literature

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