ResearchPad - hodgkin-lymphoma https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[An intronic deletion in megakaryoblastic leukemia 1 is associated with hyperproliferation of B cells in triplets with Hodgkin lymphoma]]> https://www.researchpad.co/article/elastic_article_11057 Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor and together they regulate transcription of actin cytoskeleton genes. MKL1 is associated with hematologic malignancies and immunodeficiency, but its role in B cells is unexplored. Here we examined B cells from monozygotic triplets with an intronic deletion in MKL1, two of whom had been previously treated for Hodgkin lymphoma (HL). To investigate MKL1 and B-cell responses in the pathogenesis of HL, we generated Epstein-Barr virus-transformed lymphoblastoid cell lines from the triplets and two controls. While cells from the patients with treated HL had a phenotype close to that of the healthy controls, cells from the undiagnosed triplet had increased MKL1 mRNA, increased MKL1 protein, and elevated expression of MKL1-dependent genes. This profile was associated with elevated actin content, increased cell spreading, decreased expression of CD11a integrin molecules, and delayed aggregation. Moreover, cells from the undiagnosed triplet proliferated faster, displayed a higher proportion of cells with hyperploidy, and formed large tumors in vivo. This phenotype was reversible by inhibiting MKL1 activity. Interestingly, cells from the triplet treated for HL in 1985 contained two subpopulations: one with high expression of CD11a that behaved like control cells and the other with low expression of CD11a that formed large tumors in vivo similar to cells from the undiagnosed triplet. This implies that pre-malignant cells had re-emerged a long time after treatment. Together, these data suggest that dysregulated MKL1 activity participates in B-cell transformation and the pathogenesis of HL.

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<![CDATA[Identification of a <i>miR-146b</i>-Fas ligand axis in the development of neutropenia in T large granular lymphocyte leukemia]]> https://www.researchpad.co/article/elastic_article_11033 Tlarge granular lymphocyte leukemia (T-LGLL) is characterized by the expansion of several large granular lymphocyte clones, among which a subset of large granular lymphocytes showing constitutively activated STAT3, a specific CD8+/CD4 phenotype and the presence of neutropenia has been identified. Although STAT3 is an inducer of transcription of a large number of oncogenes, so far its relationship with miRNAs has not been evaluated in T-LGLL patients. Here, we investigated whether STAT3 could carry out its pathogenetic role in T-LGLL through an altered expression of miRNAs. The expression level of 756 mature miRNA was assessed on purified T large granular lymphocytes (T-LGLs) by using a TaqMan Human microRNA Array. Hierarchical Clustering Analysis of miRNA array data shows that the global miRNome clusters with CD8 T-LGLs. Remarkably, CD8 T-LGLs exhibit a selective and STAT3-dependent repression of miR-146b expression, that significantly correlated with the absolute neutrophil counts and inversely correlated with the expression of Fas ligand (FasL), that is regarded as the most relevant factor in the pathogenesis of neutropenia. Experimental evidence demonstrates that the STAT3-dependent reduction of miR-146b expression in CD8 T-LGLs occurs as a consequence of miR-146b promoter hypermethylation and results in the disruption of the HuR-mediated post-transcriptional machinery controlling FasL mRNA stabilization. Restoring miR-146b expression in CD8 T-LGLs lead to a reduction of HuR protein and, in turn, of FasL mRNA expression, thus providing mechanistic insights for the existence of a STAT3-miR146b-FasL axis and neutropenia in T-LGLL.

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<![CDATA[CXCR4 upregulation is an indicator of sensitivity to B-cell receptor/PI3K blockade and a potential resistance mechanism in B-cell receptor-dependent diffuse large B-cell lymphomas]]> https://www.researchpad.co/article/elastic_article_11022 B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-agent BCR pathway inhibitors have had more limited activity in patients with DLBCL, underscoring the need for indicators of sensitivity to BCR blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 (CXCR4) in BCR-dependent DLBCL cell lines and primary tumors following chemical spleen tyrosine kinase (SYK) inhibition, molecular SYK depletion or chemical PI3K blockade. SYK or PI3K inhibition also selectively upregulated cell surface CXCR4 protein expression in BCR-dependent DLBCLs. CXCR4 expression was directly modulated by fork-head box O1 via the PI3K/protein kinase B/forkhead box O1 signaling axis. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased stromal cell-derived factor-1α (SDF-1α) induced chemotaxis, consistent with the role of CXCR4 signaling in B-cell migration. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sensitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.

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<![CDATA[An increase in <i>MYC</i> copy number has a progressive negative prognostic impact in patients with diffuse large B-cell and high-grade lymphoma, who may benefit from intensified treatment regimens]]> https://www.researchpad.co/article/elastic_article_11015 MYC translocations, a hallmark of Burkitt lymphoma, occur in 5-15% of diffuse large B-cell lymphoma, and have a negative prognostic impact. Numerical aberrations of MYC have also been detected in these patients, but their incidence and prognostic role are still controversial. We analyzed the clinical impact of MYC increased copy number on 385 patients with diffuse large B-cell lymphoma screened at diagnosis for MYC, BCL2, and BCL6 rearrangements. We enumerated the number of MYC copies, defining as amplified those cases with an uncountable number of extra-copies. The prevalence of MYC translocation, increased copy number and amplification was 8.8%, 15%, and 1%, respectively. Patients with 3 or 4 gene copies, accounting for more than 60% of patients with MYC copy number changes, had a more favorable outcome compared to patients with >4 copies or translocation of MYC, and were not influenced by the type of treatment received as first-line. Stratification according to the number of MYC extra-copies showed a negative correlation between an increasing number of copies and survival. Patients with >7 copies or the amplification of MYC had the poorest prognosis. Patients with >4 copies of MYC showed a similar, trending towards worse prognosis compared to patients with MYC translocation. The survival of patients with >4 copies, translocation or amplification of MYC seemed to be superior if intensive treatments were used. Our study underlines the importance of fluorescence in situ hybridization testing at diagnosis of diffuse large B-cell lymphoma to detect the rather frequent and clinically significant numerical aberrations of MYC.

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<![CDATA[miR-497 suppresses cycle progression through an axis involving CDK6 in ALK-positive cells]]> https://www.researchpad.co/article/5c756312d5eed0c484cb74f7

Anaplastic large-cell lymphoma, a T-cell neoplasm, is primarily a pediatric disease. Seventy-five percent of pediatric anaplastic large-cell lymphoma cases harbor the chromosomal translocation t(2;5)(p23;q35) leading to the ectopic expression of NPM-ALK, a chimeric tyrosine kinase. NPM-ALK consists of an N-terminal nucleophosmin (NPM) domain fused to an anaplastic lymphoma kinase (ALK) cytoplasmic domain. Pediatric NPM-ALK+ anaplastic large-cell lymphoma is often a disseminated disease and young patients are prone to chemoresistance or relapse shortly after chemotherapeutic treatment. Furthermore, there is no gold standard protocol for the treatment of relapses. To the best of our knowledge, this is the first study on the potential role of the microRNA, miR-497, in NPM-ALK+ anaplastic large-cell lymphoma tumorigenesis. Our results show that miR-497 expression is repressed in NPM-ALK+ cell lines and patient samples through the hypermethylation of its promoter and the activity of NPM-ALK is responsible for this epigenetic repression. We demonstrate that overexpression of miR-497 in human NPM-ALK+ anaplastic large-cell lymphoma cells inhibits cellular growth and causes cell cycle arrest by targeting CDK6, E2F3 and CCNE1, the three regulators of the G1 phase of the cell cycle. Interestingly, we show that a scoring system based on CDK6, E2F3 and CCNE1 expression could help to identify relapsing pediatric patients. In addition, we demonstrate the sensitivity of NPM-ALK+ cells to CDK4/6 inhibition using for the first time a selective inhibitor, palbociclib. Together, our findings suggest that CDK6 could be a therapeutic target for the development of future treatments for NPM-ALK+ anaplastic large-cell lymphoma.

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<![CDATA[Prognostic value of baseline metabolic tumor volume and total lesion glycolysis in patients with lymphoma: A meta-analysis]]> https://www.researchpad.co/article/5c3fa583d5eed0c484ca53ef

Whether baseline metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) measured by FDG-PET/CT affected prognosis of patients with lymphoma was controversial. We searched PubMed, EMBASE and Cochrane to identify studies assessing the effect of baseline TMTV and TLG on the survival of lymphoma patients. Pooled hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) were calculated, along with 95% confidence intervals (CI). Twenty-seven eligible studies including 2,729 patients were analysed. Patients with high baseline TMTV showed a worse prognosis with an HR of 3.05 (95% CI 2.55–3.64, p<0.00001) for PFS and an HR of 3.07 (95% CI 2.47–3.82, p<0.00001) for OS. Patients with high baseline TLG also showed a worse prognosis with an HR of 3.44 (95% CI 2.37–5.01, p<0.00001) for PFS and an HR of 3.08 (95% CI 1.84–5.16, p<0.00001) for OS. A high baseline TMTV was significantly associated with worse survival in DLBCL patients treated with R-CHOP (OS, pooled HR = 3.52; PFS, pooled HR = 2.93). A high baseline TLG was significantly associated with worse survival in DLBCL patients treated with R-CHOP (OS, pooled HR = 3.06; PFS, pooled HR = 2.93). The negative effect of high baseline TMTV on PFS was demonstrated in HL (pooled HR = 3.89). A high baseline TMTV was significantly associated with worse survival in ENKL patients (OS, pooled HR = 2.24; PFS, pooled HR = 3.25). A high baseline TLG was significantly associated with worse survival in ENKL patients (OS, pooled HR = 2.58; PFS, pooled HR = 2.99). High baseline TMTV or TLG predict significantly worse PFS and OS in patients with lymphoma. Future studies are warranted to explore whether TMTV or TLG could be integrated into various prognostic models for clinical decision making.

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<![CDATA[Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma]]> https://www.researchpad.co/article/5c1c2d97d5eed0c484464794

Aberrant changes in microRNA expression contribute to lymphomagenesis. Bromodomain and extra-terminal domain inhibitors such as OTX015 (MK-8628, birabresib) have demonstrated preclinical and clinical activity in hematologic tumors. MicroRNA profiling of diffuse large B-cell lymphoma cells treated with OTX015 revealed changes in the expression levels of a limited number of microRNAs, including miR-92a-1-5p, miR-21-3p, miR-155-5p and miR-96-5p. Analysis of publicly available chromatin immunoprecipitation sequencing data of diffuse large B-cell lymphoma cells treated with bromodomain and extra-terminal domain (BET) inhibitors showed that the BET family member BRD4 bound to the upstream regulatory regions of multiple microRNA genes and that this binding decreased following BET inhibition. Alignment of our microRNA profiling data with the BRD4 chromatin immunoprecipitation sequencing data revealed that microRNAs downregulated by OTX015 also exhibited reduced BRD4 binding in their promoter regions following treatment with another bromodomain and extra-terminal domain inhibitor, JQ1, indicating that BRD4 contributes directly to microRNA expression in lymphoma. Treatment with bromodomain and extra-terminal domain inhibitors also decreased the expression of the arginine methyltransferase PRMT5, which plays a crucial role in B-cell transformation and negatively modulates the transcription of miR-96-5p. The data presented here indicate that in addition to previously observed effects on the expression of coding genes, bromodomain and extra-terminal domain inhibitors also modulate the expression of microRNAs involved in lymphomagenesis.

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<![CDATA[Cyclin-dependent kinase 9 as a potential specific molecular target in NK-cell leukemia/lymphoma]]> https://www.researchpad.co/article/5c1c2d9ad5eed0c4844648a5

BAY 1143572 is a highly selective inhibitor of cyclin-dependent kinase 9/positive transcription elongation factor b. It has entered phase I clinical studies. Here, we have assessed the utility of BAY 1143572 for treating natural killer (NK) cell leukemias/lymphomas that have a poor prognosis, namely extranodal NK/T-cell lymphoma, nasal type and aggressive NK-cell leukemia, in a preclinical mouse model in vivo as well as in tissue culture models in vitro. Seven NK-cell leukemia/lymphoma lines and primary aggressive NK-cell leukemia cells from two individual patients were treated with BAY 1143572 in vitro. Primary tumor cells from an aggressive NK-cell leukemia patient were used to establish a xenogeneic murine model for testing BAY 1143572 therapy. Cyclin-dependent kinase 9 inhibition by BAY 1143572 resulted in prevention of phosphorylation at the serine 2 site of the C-terminal domain of RNA polymerase II. This resulted in lower c-Myc and Mcl-1 levels in the cell lines, causing growth inhibition and apoptosis. In aggressive NK-cell leukemia primary tumor cells, exposure to BAY 1143572 in vitro resulted in decreased Mcl-1 protein levels resulting from inhibition of RNA polymerase II C-terminal domain phosphorylation at the serine 2 site. Orally administering BAY 1143572 once per day to aggressive NK-cell leukemia-bearing mice resulted in lower tumor cell infiltration into the bone marrow, liver, and spleen, with less export to the periphery relative to control mice. The treated mice also had a survival advantage over the untreated controls. The specific small molecule targeting agent BAY1143572 has potential for treating NK-cell leukemia/lymphoma.

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<![CDATA[Antiviral Treatment of HCV-Infected Patients with B-Cell Non-Hodgkin Lymphoma: ANRS HC-13 Lympho-C Study]]> https://www.researchpad.co/article/5989d9faab0ee8fa60b7181d

Hepatitis C virus (HCV) infection is associated with lymphoproliferative disorders and B-cell non-Hodgkin lymphomas (B-NHLs). Evaluation of the efficacy and safety profiles of different antiviral therapies in HCV patients with B-NHL is warranted. Methods: First, we evaluated the sustained virologic response (SVR) and safety of Peg-interferon-alpha (Peg-IFN) + ribavirin +/- first protease inhibitors (PI1s) therapy in 61 HCV patients with B-NHL enrolled in a nationwide observational survey compared with 94 matched HCV-infected controls without B-NHL. In a second series, interferon-free regimens using a newly optimal combination therapy with direct-acting antiviral drugs (DAAs) were evaluated in 10 patients with HCV and B-NHL. Results: The main lymphoma type was diffuse large B-cell lymphoma (38%) followed by marginal zone lymphoma (31%). In the multivariate analysis, patients with B-NHL treated by Peg-IFN-based therapy exhibited a greater SVR rate compared with controls, 50.8% vs 30.8%, respectively, p<0.01, odds ratio (OR) = 11.2 [2.3, 52.8]. B-NHL response was better (p = 0.02) in patients with SVR (69%) than in patients without SVR (31%). Premature discontinuation of Peg-IFN-based therapy was significantly more frequent in the B-NHL group (19.6%) compared with the control group (6.3%), p<0.02. Overall, survival was significantly enhanced in the controls than in the B-NHL group (hazard ratio = 34.4 [3.9, 304.2], p< 0.01). Using DAAs, SVR was achieved in 9/10 patients (90%). DAAs were both well tolerated and markedly efficient. Conclusions: The virologic response of HCV-associated B-NHL is high. Our study provides a comprehensive evaluation of different strategies for the antiviral treatment of B-NHL associated with HCV infection.

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<![CDATA[Overview and outcome of Hodgkin’s Lymphoma: Experience of a single developing country’s oncology centre]]> https://www.researchpad.co/article/5bfed86cd5eed0c4849db253

Hodgkin’s Lymphoma (HL) reveals variable epidemiological and clinico-pathological features in different geographical locations. In this retrospective study, we aimed to assess the epidemiological and clinic-pathological features, and outcome of HL patients treated at one hemato-oncology centre in Erbil, northern Iraq. Medical records of 103 HL patients treated over more than six years were reviewed. Treatment outcome was evaluated by measuring the 5-year overall and progression-free survival rates. The median age of patients was 23 years, children up to 17 years constituted 31.1%, and male to female ratio was 1:1.05. The majority (96.1%) of patients presented with lymphadenopathy. Nodular sclerosis subtype was the mostly encountered histologic type (48.5%); about half of the patients (49.5%) had stage II disease. Relapse occurred in 20 patients; the 5-year overall survival for children was better (89%) compared to adult patients (79%). The associated risk features found to have adverse effects on the survival, however, only high LDH level and presence of B-symptoms at presentation showed significant correlation. The epidemiological and clinical characteristics of HL in our locality followed the pattern in the western world. The 5-year overall and progression-free survivals were far below the international rates, a matter which may necessitate a revision to HL treatment strategy at our centre.

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<![CDATA[Can We Spare the Pancreas and Other Abdominal Organs at Risk? A Comparison of Conformal Radiotherapy, Helical Tomotherapy and Proton Beam Therapy in Pediatric Irradiation]]> https://www.researchpad.co/article/5989daf1ab0ee8fa60bc154e

Objectives

Late abdominal irradiation toxicity during childhood included renal damage, hepatic toxicity and secondary diabetes mellitus. We compared the potential of conformal radiotherapy (CRT), helical tomotherapy (HT) and proton beam therapy (PBT) to spare the abdominal organs at risk (pancreas, kidneys and liver- OAR) in children undergoing abdominal irradiation.

Methods

We selected children with abdominal tumors who received more than 10 Gy to the abdomen. Treatment plans were calculated in order to keep the dose to abdominal OAR as low as possible while maintaining the same planned target volume (PTV) coverage. Dosimetric values were compared using the Wilcoxon signed-rank test.

Results

The dose distribution of 20 clinical cases with a median age of 8 years (range 1–14) were calculated with different doses to the PTV: 5 medulloblastomas (36 Gy), 3 left-sided and 2 right-sided nephroblastomas (14.4 Gy to the tumor + 10.8 Gy boost to para-aortic lymphnodes), 1 left-sided and 4 right-sided or midline neuroblastomas (21 Gy) and 5 Hodgkin lymphomas (19.8 Gy to the para-aortic lymphnodes and spleen). HT significantly reduced the mean dose to the whole pancreas (WP), the pancreatic tail (PT) and to the ipsilateral kidney compared to CRT. PBT reduced the mean dose to the WP and PT compared to both CRT and HT especially in midline and right-sided tumors. PBT decreased the mean dose to the ispilateral kidney but also to the contralateral kidney and the liver compared to CRT. Low dose to normal tissue was similar or increased with HT whereas integral dose and the volume of normal tissue receiving at least 5 and 10 Gy were reduced with PBT compared to CRT and HT.

Conclusion

In children undergoing abdominal irradiation therapy, proton beam therapy reduces the dose to abdominal OAR while sparing normal tissue by limiting low dose irradiation.

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<![CDATA[Variation in Dicer Gene Is Associated with Increased Survival in T-Cell Lymphoma]]> https://www.researchpad.co/article/5989dadfab0ee8fa60bbb1bc

Dicer, an endonuclease in RNase III family, is essential for the RNA interference (RNAi) pathway. Aberrant expression of Dicer has been shown in various cancers including some subtypes of T cell lymphoma (TCL), which influences patient prognosis. A single-nucleotide polymorphism (SNP) rs3742330A>G has been identified in the Dicer gene, located in the 3′ untranslated region (3′ UTR) that is important for mRNA transcript stability. We investigated whether rs3742330 is associated with the survival in 163 TCL patients. Significant association between Dicer rs3742330 and TCL survival were found. Patients carrying the GG genotype (n = 12) had a significantly increased overall survival (OS) compared with those carrying the GA and AA genotypes (n = 70 and n = 81, respectively; p = 0.031). Moreover, the significant association was maintained for patients with mature T type (n = 134; p = 0.026). In multivariate Cox-regression analysis, rs3742330 proved to be an independent predictor for OS, together with the commonly used International Prognostic Index (IPI) and BAFF rs9514828, another SNP we have previously reported to be associated with TCL survival, with hazard ratios (HRs) for patient death rate of 8.956 (95% CI, 1.210 to 66.318; p = 0.032) for the GA genotype and 10.145 (95% CI, 1.371 to 75.084; p = 0.023) for the AA genotype. Furthermore, we observed cumulative effects of Dicer rs3742330 and BAFF rs9514828 on TCL survival. Compared with patients carrying zero unfavorable genotype, those carrying one and two unfavorable genotypes had an increased risk of death with a HR of 7.104 (95% CI, 0.969–53.086; p = 0.054) and 14.932 (95% CI, 1.950–114.354; p = 0.009), respectively, with a significant dose-response trend (ptrend  = 0.004). In conclusion, Dicer rs3742330 is associated with TCL survival, suggesting that genetic variation might play a role in predicting prognosis of TCL patients.

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<![CDATA[Rate of Primary Refractory Disease in B and T-Cell Non-Hodgkin’s Lymphoma: Correlation with Long-Term Survival]]> https://www.researchpad.co/article/5989d9feab0ee8fa60b72ff8

Background

Primary refractory disease is a main challenge in the management of non-Hodgkin’s Lymphoma (NHL). This survey was performed to define the rate of refractory disease to first-line therapy in B and T-cell NHL subtypes and the long-term survival of primary refractory compared to primary responsive patients.

Methods

Medical records were reviewed of 3,106 patients who had undergone primary treatment for NHL between 1982 and 2012, at the Hematology Centers of Torino and Bergamo, Italy. Primary treatment included CHOP or CHOP-like regimens (63.2%), intensive therapy with autograft (16.9%), or other therapies (19.9%). Among B-cell NHL, 1,356 (47.8%) received first-line chemotherapy with rituximab. Refractory disease was defined as stable/progressive disease, or transient response with disease progression within six months.

Results

Overall, 690 (22.2%) patients showed primary refractory disease, with a higher incidence amongst T-cell compared to B-cell NHL (41.9% vs. 20.5%, respectively, p<0.001). Several other clinico-pathological factors at presentation were variably associated with refractory disease, including histological aggressive disease, unfavorable clinical presentation, Bone Marrow involvement, low lymphocyte/monocyte ration and male gender. Amongst B-cell NHL, the addition of rituximab was associated with a marked reduction of refractory disease (13.6% vs. 26.7% for non-supplemented chemotherapy, p<0.001). Overall, primary responsive patients had a median survival of 19.8 years, compared to 1.3 yr. for refractory patients. A prolonged survival was consistently observed in all primary responsive patients regardless of the histology. The long life expectancy of primary responsive patients was documented in both series managed before and after 2.000. Response to first line therapy resulted by far the most predictive factor for long-term outcome (HR for primary refractory disease: 16.52, p<0.001).

Conclusion

Chemosensitivity to primary treatment is crucial for the long-term survival in NHL. This supports the necessity of studies aimed to early identify refractory disease and to develop different treatment strategies for responsive and refractory patients.

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<![CDATA[Epidemiology of Classical Hodgkin Lymphoma and Its Association with Epstein Barr Virus in Northern China]]> https://www.researchpad.co/article/5989da94ab0ee8fa60ba1497

Background

The incidence of classical Hodgkin lymphoma (cHL) and its association with Epstein-Barr virus (EBV) varies significantly with age, sex, ethnicity and geographic location. This is the first report on epidemiological features of cHL patients from Northern regions of China. These features are compared to data from a previously published Dutch cHL population.

Methodology/Principal Findings

157 cHL patients diagnosed between 1997 and 2008 in the North of China were included after histopathological re-evaluation. The Dutch population-based cohort consisted of 515 cHL patients diagnosed between 1987 and 2000. EBV status was determined by in situ hybridization of EBV- encoded small RNAs. In the Chinese population, tumor cells of 39% of the cHL patients were EBV+ and this was significantly associated with male sex, mixed cellularity subtype and young age (<20 y). The median age of the Chinese patients was 9 years younger than that of the Dutch patients (28 y vs. 37 y). In addition, the age distribution between the two populations was strikingly different in both the EBV+ subgroups (p<0.001) and the EBV- subgroups (p = 0.01). The mixed cellularity subtype was almost 3x more frequent amongst the Chinese (p<0.001).

Conclusion/Significance

CHL patients from Northern regions of China show a distinctive age distribution pattern with a striking incidence peak of EBV+ mixed cellularity cases among children and adolescents and another high incidence peak of EBV- nodular sclerosis cases in young adults. In comparison to Dutch cHL patients there are pronounced differences in age distribution, subtype and EBV status, presumably caused by complex gene-environmental interactions.

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<![CDATA[HLA expression and HLA type associations in relation to EBV status in Hispanic Hodgkin lymphoma patients]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdbfb7

A proportion of classical Hodgkin lymphomas harbor the Epstein Barr virus (EBV). We previously demonstrated that associations between Human Leukocyte Antigen (HLA) alleles and susceptibility to EBV+ classical Hodgkin lymphoma differ between European and Chinese populations. Data on Hispanic populations is missing. Here we examined the association between HLA type, tumor cell HLA expression and other characteristics in Hispanic Hodgkin lymphoma patients. Hispanic Hodgkin lymphoma patients diagnosed at the Los Angeles County-University of Southern California Medical Center from 2000–2012 were included (n = 65). Formalin-fixed paraffin-embedded tumor tissue was analyzed for EBV by in situ hybridization and for HLA class I and class II expression by immunohistochemistry. HLA typing was performed by HLA-A specific quantitative PCR of genomic DNA from tissue. Thirty patients (46%) had EBV+ tumors. Expression of HLA class I (p = 0.0006) was significantly associated with EBV+ tumor status in Hispanic patients, similar to Europeans and Chinese. A positive association between HLA class II expression and EBV+ tumor status, as present in large studies in Europeans, was not found (p = 0.06). The prevalences of the specific European HLA-A*01 risk and European HLA-A*02 protective types were not significantly associated with EBV+ tumors among these Hispanic patients, however numbers were too low to draw firm conclusions. The HLA-A*02:07 allele, that is associated with EBV+ Hodgkin lymphoma in Chinese, was absent. In conclusion, the association between EBV positivity in tumor cells and HLA class I expression appears to be consistent across different populations. Larger studies in Hispanics are needed to evaluate HLA allele susceptibility associations.

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<![CDATA[Genome-Wide Detection of Genes Targeted by Non-Ig Somatic Hypermutation in Lymphoma]]> https://www.researchpad.co/article/5989da87ab0ee8fa60b9c6c3

The processes of somatic hypermutation (SHM) and class switch recombination introduced by activation-induced cytosine deaminase (AICDA) at the Immunoglobulin (Ig) loci are key steps for creating a pool of diversified antibodies in germinal center B cells (GCBs). Unfortunately, AICDA can also accidentally introduce mutations at bystander loci, particularly within the 5′ regulatory regions of proto-oncogenes relevant to diffuse large B cell lymphomas (DLBCL). Since current methods for genomewide sequencing such as Exon Capture and RNAseq only target mutations in coding regions, to date non-Ig promoter SHMs have been studied only in a handful genes. We designed a novel approach integrating bioinformatics tools with next generation sequencing technology to identify regulatory loci targeted by SHM genome-wide. We observed increased numbers of SHM associated sequence variant hotspots in lymphoma cells as compared to primary normal germinal center B cells. Many of these SHM hotspots map to genes that have not been reported before as mutated, including BACH2, BTG2, CXCR4, CIITA, EBF1, PIM2, and TCL1A, etc., all of which have potential roles in B cell survival, differentiation, and malignant transformation. In addition, using BCL6 and BACH2 as examples, we demonstrated that SHM sites identified in these 5′ regulatory regions greatly altered their transcription activities in a reporter assay. Our approach provides a first cost-efficient, genome-wide method to identify regulatory mutations and non-Ig SHM hotspots.

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<![CDATA[Role of Smad Proteins in Resistance to BMP-Induced Growth Inhibition in B-Cell Lymphoma]]> https://www.researchpad.co/article/5989db40ab0ee8fa60bd6aa3

Bone morphogenetic protein (BMP) expression and signaling are altered in a variety of cancers, but the functional impact of these alterations is uncertain. In this study we investigated the impact of expression of multiple BMPs and their signaling pathway components in human B-cell lymphoma. BMP messages, in particular BMP7, were detected in normal and malignant B cells. Addition of exogenous BMPs inhibited DNA synthesis in most lymphoma cell lines examined, but some cell lines were resistant. Tumor specimens from three out of five lymphoma patients were also resistant to BMPs, as determined by no activation of the BMP effectors Smad1/5/8. We have previously shown that BMP-7 potently induced apoptosis in normal B cells, which was in contrast to no or little inhibitory effect of this BMP in the lymphoma cells tested. BMP-resistance mechanisms were investigated by comparing sensitive and resistant cell lines. While BMP receptors are downregulated in many cancers, we documented similar receptor levels in resistant and sensitive lymphoma cells. We found a positive correlation between activation of Smad1/5/8 and inhibition of DNA synthesis. Gene expression analysis of two independent data sets showed that the levels of inhibitory Smads varied across different B-cell lymphoma. Furthermore, stable overexpression of Smad7 in two different BMP-sensitive cell lines with low endogenous levels of SMAD7, rendered them completely resistant to BMPs. This work highlights the role of Smads in determining the sensitivity to BMPs and shows that upregulation of Smad7 in cancer cells is sufficient to escape the negative effects of BMPs.

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<![CDATA[Proteomic Profiling of a Mouse Model for Ovarian Granulosa Cell Tumor Identifies VCP as a Highly Sensitive Serum Tumor Marker in Several Human Cancers]]> https://www.researchpad.co/article/5989d9daab0ee8fa60b673ef

The initial aim of this study was to identify novel serum diagnostic markers for the human ovarian granulosa cell tumor (GCT), a tumor that represents up to 5% of all ovarian cancers. To circumvent the paucity of human tissues available for analyses, we used the Ctnnb1tm1Mmt/+;Ptentm1Hwu/tmiHwu;Amhr2tm3(cre)Bhr/+ transgenic mouse model, which features the constitutive activation of CTNNB1 signaling combined with the loss of Pten in granulosa cells and develops GCTs that mimic aggressive forms of the human disease. Proteomic profiling by mass spectrometry showed that vinculin, enolase 1, several heat shock proteins, and valosin containing protein (VCP) were more abundantly secreted by cultured mouse GCT cells compared to primary cultured GC. Among these proteins, only VCP was present in significantly increased levels in the preoperative serum of GCT cancer patients compared to normal subjects. To determine the specificity of VCP, serum levels were also measured in ovarian carcinoma, non-Hodgkin's lymphoma and breast, colon, pancreatic, lung, and prostate cancer patients. Increased serum VCP levels were observed in the majority of cancer cases, with the exception of patients with lung or prostate cancer. Moreover, serum VCP levels were increased in some GCT, ovarian carcinoma, breast cancer, and colon cancer patients who did not otherwise display increased levels of widely used serum tumor markers for their cancer type (e.g. inhibin A, inhibin B, CA125, CEA, or CA15.3). These results demonstrate the potential use of VCP as highly sensitive serum marker for GCT as well as several other human cancers.

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<![CDATA[Lestaurtinib Inhibition of the JAK/STAT Signaling Pathway in Hodgkin Lymphoma Inhibits Proliferation and Induces Apoptosis]]> https://www.researchpad.co/article/5989da26ab0ee8fa60b80bd3

Standard cytotoxic chemotherapy for Hodgkin Lymphoma (HL) has changed little in 30 years; the treatment for patients with relapsed or refractory disease remains challenging and novel agents are under development. JAK/STAT constitutive activation plays an important role in the pathogenesis of HL. Lestaurtinib is an orally bioavailable multikinase inhibitor that has recently been shown to inhibit JAK2 in myeloproliferative disorders. The potential role of Lestaurtinib in HL therapy is unknown. We have analyzed the effect of Lestaurtinib treatment in five HL cell lines from refractory patients, L-428, L-1236, L-540, HDML-2 and HD-MY-Z. At 48 h, a dose-dependent cell growth inhibition (23%–66% at 300 nM) and apoptotic increment (10%–64% at 300 nM) were observed. Moreover, Lestaurtinib inhibited JAK2, STAT5 and STAT3 phosphorylation and reduced the mRNA expression of its downstream antiapoptotic target Bcl-xL. In addition, we have analyzed the effect of Lestaurtinib treatment in lymph nodes from four classic HL patients. We observed a decrease in cell viability at 24 hours of treatment in three patients (mean decrease of 27% at 300 nM). Our findings provide, for the first time, a molecular rationale for testing JAK2 inhibitors, specifically Lestaurtinib, in HL patients.

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<![CDATA[Oligomeric Structure of the MALT1 Tandem Ig-Like Domains]]> https://www.researchpad.co/article/5989db15ab0ee8fa60bcce87

Background

Mucosa-associated lymphoid tissue 1 (MALT1) plays an important role in the adaptive immune program. During TCR- or BCR-induced NF-κB activation, MALT1 serves to mediate the activation of the IKK (IκB kinase) complex, which subsequently regulates the activation of NF-κB. Aggregation of MALT1 is important for E3 ligase activation and NF-κB signaling.

Principal Findings

Unlike the isolated CARD or paracaspase domains, which behave as monomers, the tandem Ig-like domains of MALT1 exists as a mixture of dimer and tetramer in solution. High-resolution structures reveals a protein-protein interface that is stabilized by a buried surface area of 1256 Å2 and contains numerous hydrogen and salt bonds. In conjunction with a second interface, these interactions may represent the basis of MALT1 oligomerization.

Conclusions

The crystal structure of the tandem Ig-like domains reveals the oligomerization potential of MALT1 and a potential intermediate in the activation of the adaptive inflammatory pathway.

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