scholarly journals High ETV6 Levels Support Aggressive B Lymphoma Cell Survival and Predict Poor Outcome in Diffuse Large B-Cell Lymphoma Patients

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 338
Author(s):  
Dario Marino ◽  
Marco Pizzi ◽  
Iuliia Kotova ◽  
Ronny Schmidt ◽  
Christoph Schröder ◽  
...  
Keyword(s):  
B Cell ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
Inverse Correlation ◽  
B Cell Lymphoma ◽  
Cox Regression Analysis ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

The identification of prognostic factors for aggressive B-cell lymphomas still represents an unmet clinical need. We used forward phase protein arrays (FFPA) to identify proteins associated with overall survival (OS) from diagnostic formalin-fixed paraffin-embedded material of diffuse large B-cell lymphoma (DLBCL) patients (n = 47). Univariate Cox regression analysis identified numerous proteins, including immune check-point molecules (PDCD1, PDCD2 and PD1L2) and BCL2 to be significantly associated with OS. However, only ETV6 and PIM2 proteins persisted following multivariate Cox analysis. Independent validation studies by immunohistochemistry and analysis of public gene expression profiles of DLBCL confirmed a prognostic role for high ETV6 and ETV6/PIM2 ratios in DLBCL. ETV6 is a recurrently mutated/deleted gene in DLBCL for which its function in this disease entity is currently unknown. We find that ETV6 is upregulated during oncogenic transformation of germinal center B-cells and that it regulates DLBCL survival, as its acute loss results in marked apoptosis. Fluctuations in survivin (BIRC5) expression levels were associated with this phenomenon. Furthermore, an inverse correlation between ETV6 and BIRC5 expression levels was found and correlated with a response to the BIRC5 inhibitor, YM155. In conclusion, we present evidence for an oncogenic function of ETV6 in DLBCL.

miRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy

Blood ◽  
2011 ◽  
Vol 118 (4) ◽  
pp. 1034-1040 ◽  
Author(s):  
Santiago Montes-Moreno ◽  
Nerea Martinez ◽  
Beatriz Sanchez-Espiridión ◽  
Ramon Díaz Uriarte ◽  
Maria Elena Rodriguez ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Mirna Expression ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
Test Group ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) prognostication requires additional biologic markers. miRNAs may constitute markers for cancer diagnosis, outcome, or therapy response. In the present study, we analyzed the miRNA expression profile in a retrospective multicenter series of 258 DLBCL patients uniformly treated with chemoimmunotherapy. Findings were correlated with overall survival (OS) and progression-free survival (PFS). miRNA and gene-expression profiles were studied using microarrays in an initial set of 36 cases. A selection of miRNAs associated with either DLBCL molecular subtypes (GCB/ABC) or clinical outcome were studied by multiplex RT-PCR in a test group of 240 cases with available formalin-fixed, paraffin-embedded (FFPE) diagnostic samples. The samples were divided into a training set (123 patients) and used to derive miRNA-based and combined (with IPI score) Cox regression models in an independent validation series (117 patients). Our model based on miRNA expression predicts OS and PFS and improves upon the predictions based on clinical variables. Combined models with IPI score identified a high-risk group of patients with a 2-year OS and a PFS probability of < 50%. In summary, a precise miRNA signature is associated with poor clinical outcome in chemoimmunotherapy-treated DLBCL patients. This information improves upon IPI-based predictions and identifies a subgroup of candidate patients for alternative therapeutic regimens.

scholarly journals The role of рАКТ1 expression in diffuse large B-cell lymphoma

2021 ◽  
Vol 20 (3) ◽  
pp. 13-20
Author(s):  
E. V. Vaneeva ◽  
V. A. Rosin ◽  
D. A. Diakonov ◽  
A. S. Luchinin ◽  
S. V. Samarina ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cox Regression Analysis ◽  
Large B Cell Lymphoma ◽  
Long Term Treatment ◽  
The Impact ◽  
Large B Cell

Aim. To evaluate the prognostic value of pAKT1 expression by tumor cells in patients with diffuse large B-cell lymphoma.Materials and methods. The study included 90 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL), who were treated at the clinic of Kirov Research Institute of Hematology and Blood Transfusion from 2014 to 2017 and received standard first-line polychemotherapy according to the R-CHOP regimen. Using immunohistochemical and morphometric methods, the relative number of tumor cells expressing pAKT1 was determined. Using the two-sided Fisher’s exact test, the relationship of different levels of marker expression with clinical and laboratory parameters of patients and long-term treatment results was analyzed. The impact of pAKT1 on the risk of an adverse event was assessed using the Cox regression analysis.Results. Overexpression of pAKT1 is associated with unfavorable clinical characteristics of patients with DLBCL, excessive expression of the BCL2 and c-Myc oncoproteins, as well as with low rates of overall and progressive survival. Overexpression of pAKT1 is an independent prognostic factor and statistically significantly affects the risk of an adverse outcome in DLBCL.Conclusion. The degree of pAKT1 expression is an informative criterion that allows to predict the course of diffuse large B-cell lymphoma. It is advisable to use the indicated marker when stratifying patients into risk groups.

scholarly journals Circulating long non-coding RNAs HOTAIR, Linc-p21, GAS5 and XIST expression profiles in diffuse large B-cell lymphoma: association with R-CHOP responsiveness

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahmoud A. Senousy ◽  
Aya M. El-Abd ◽  
Raafat R. Abdel-Malek ◽  
Sherine M. Rizk
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Diagnostic Tools ◽  
Large B Cell Lymphoma ◽  
Non Coding Rnas ◽  
Large B Cell

AbstractThe reliable identification of diffuse large B-cell lymphoma (DLBCL)-specific targets owns huge implications for its diagnosis and treatment. Long non-coding RNAs (lncRNAs) are implicated in DLBCL pathogenesis; however, circulating DLBCL-related lncRNAs are barely investigated. We investigated plasma lncRNAs; HOTAIR, Linc-p21, GAS5 and XIST as biomarkers for DLBCL diagnosis and responsiveness to R-CHOP therapy. Eighty-four DLBCL patients and thirty-three healthy controls were included. Only plasma HOTAIR, XIST and GAS5 were differentially expressed in DLBCL patients compared to controls. Pretreatment plasma HOTAIR was higher, whereas GAS5 was lower in non-responders than responders to R-CHOP. Plasma GAS5 demonstrated superior diagnostic accuracy (AUC = 0.97) whereas a panel of HOTAIR + GAS5 superiorly discriminated responders from non-responders by ROC analysis. In multivariate analysis, HOTAIR was an independent predictor of non-response. Among patients, plasma HOTAIR, Linc-p21 and XIST were correlated. Plasma GAS5 negatively correlated with International Prognostic Index, whereas HOTAIR positively correlated with performance status, denoting their prognostic potential. We constructed the lncRNAs-related protein–protein interaction networks linked to drug response via bioinformatics analysis. In conclusion, we introduce plasma HOTAIR, GAS5 and XIST as potential non-invasive diagnostic tools for DLBCL, and pretreatment HOTAIR and GAS5 as candidates for evaluating therapy response, with HOTAIR as a predictor of R-CHOP failure. We provide novel surrogates for future predictive studies in personalized medicine.

scholarly journals DNMT3A-2 EXPRESSION LEVELS CHARACTERISE DIFFUSE LARGE B-CELL LYMPHOMA WITH DISTINCT METHYLATION PATTERNS AND OUTCOME

2017 ◽  
Vol 35 ◽  
pp. 154-154
Author(s):  
A. Kuhnl ◽  
R. Shaikh ◽  
D. Cunningham ◽  
N. Counsell ◽  
S. Barrans ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Methylation Patterns ◽  
Large B Cell

scholarly journals Prognostic Significance of Pretreatment Neutrophil/Lymphocyte Ratio and Platelet/Lymphocyte Ratio in Patients with Diffuse Large B-Cell Lymphoma

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Siqian Wang ◽  
Yongyong Ma ◽  
Lan Sun ◽  
Yifen Shi ◽  
Songfu Jiang ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
B Cell ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Prognostic Significance ◽  
B Cell Lymphoma ◽  
Cox Regression Analysis ◽  
Lymphocyte Ratio ◽  
Large B Cell Lymphoma ◽  
Large B Cell

It is generally believed that there is correlation between cancer prognosis and pretreatment PLR and NLR. However, there are limited data about their role in diffuse large B cell lymphoma (DLBCL). This study aims to determine the prognostic value of pretreatment PLR and NLR for patients who have DLBCL. The associations between clinical characteristics and NLR and PLR were evaluated among 182 DLBCL patients from January 2005 to June 2016. The optimal cutoff values for high PLR (⩾150) and NLR (⩾2.32) in prognosis prediction were determined. The effect of NLR and PLR on survival was evaluated through multivariate Cox regression analysis, univariate analysis, and log-rank test. According to the evaluation results, patients with high NLR and PLR had significantly shorter OS (P=0.026 and P=0.035) and PFS (P=0.024 and P=0.022) compared with those who have low PLR and NLR. On multivariate analyses, IPI>2, elevated LDH, and PLR⩾2.32 were prognostic factors for OS and PFS in DLBCL patients. Therefore, we demonstrated that high PLR and NLR predicted adverse prognostic factors in DLBCL patients.

Distinct Gene Expression Profiles: Nodal versus Extranodal Diffuse Large B-Cell Lymphoma

Oncology ◽  
2008 ◽  
Vol 75 (1-2) ◽  
pp. 71-80 ◽  
Author(s):  
Zeenath Jehan ◽  
Abdul K. Siraj ◽  
Jehad Abubaker ◽  
Christian Ruiz ◽  
Ronald Simon ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
B Cell Lymphoma ◽  
Distinct Gene ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Regulation of p27 by S-Phase Kinase- Associated Protein 2 Is Associated with Aggressiveness in Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3760-3760
Author(s):  
Ritsuko Seki ◽  
Koichi Ohshima ◽  
Tomoaki Fujisaki ◽  
Naokuni Uike ◽  
Fumio Kawano ◽  
...  
Keyword(s):  
B Cell ◽  
Cox Regression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
S Phase ◽  
Prognostic Impact ◽  
Treatment Groups ◽  
Skp2 Expression ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 and p27 expression in diffuse large B cell lymphoma (DLBCL) treated with CHOP or CHOP-R. All patients (671) were diagnosed as having DLBCL at the twenty different hospitals and were treated with either CHOP (425) or CHOP-R (246) from 1996 to 2005. All specimens were histopathologically recomfirmed by one pathologist with expertise before entering into this study. Their clinical characteristics, including either the IPI or R-IPI factors, were evenly matched in both treatment groups. The median follow-up of living patients was 3.7 and 2.1 y for CHOP vs CHOP-R, respectively. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. There were 257 patients with high Skp2 expression (cutoff value >40% positive cells) (257/671,39.0%). High Skp2 expression was found in all IPI groups. Expression of p27 (P<.001) was associated with better overall survival (OS), whereas expression of Skp2 was associated with worse OS in CHOP treatment groups (P<.001). We also examined the prognostic impact of Skp2 according to various expression degree of Skp2, Skp2 expression remained a significant predictor of survival (<40%,40–79%,≥80%, P<.001). The multivariant analysis revealed that both the IPI score and the expression of Skp2 and p27 were independent predictors of OS and PFS in both treatment groups (P<.001). The patients with high Skp2 expression in combination with low p27 expression were related to worst survival in CHOP group (Fig1A). Interestingly, even in CHOP-R group, both high Skp2 expression and low p27 expression were the strong biomarker of worse prognosis (Fig 1B). DLBCL patients with high Skp2 expression did not benefit from the addition of R to CHOP. Conclusion: Addition of rituximab did not provide a beneficial outcome to DLBCL with high Skp2 and low p27 expression. Therapeutic strategies other than CHOP-R will be needed for DLBCL patients exhibiting a high Skp2 and low p27 expression at the time of diagnosis. Figure Figure

Loss of IRF8 Inhibits the Growth of Diffuse Large B-Cell Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3004-3004
Author(s):  
Yulian Xu ◽  
Lei Jiang ◽  
Rachel R. Fang ◽  
Jeff Xiwu Zhou ◽  
Herbert Morse
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Cell Lymphoma ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Expression Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract IRF8 is a transcription factor with a critical role in B lymphocyte development and biological functions. Although it has been reported that IRF8 is highly expressed in human diffuse large B-cell lymphoma (DLBCL) and the translocation of IRF8-IgH loci occurs in DLBCL, little information is available regarding the function and mechanisms for the role of IRF8 in DLBCL. In this study, by using several human DLBCL cell lines with shRNA-mediated decrease in IRF8 expression levels, we found that the loss of IRF8 significantly reduced the proliferation of lymphoma cells (Figure 1). Mechanistically, decreasing the levels of IRF8 led to a decrease in p38 and ERK phosphorylation (Figure 2), molecular events critical for B cell proliferation. Furthermore, using a xenograft lymphoma mice model, we found that the loss of IRF8 significantly inhibited the growth of lymphomas in vivo (n=5 for each group) (Figure 3). Analysis of public available data also suggested that the expression levels of IRF8 mRNA in human DLBCL tissues were inversely correlated patientsÕ overall survival time. Taken together, this study showed that IRF8 may play an oncogenic role in human DLBCL by promoting cell proliferation. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 1. Loss of IRF8 decreased the proliferation of DLBCL cells in vitro. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 2. Loss of IRF8 decreased the phosphorylation of p38 and ERK in DLBCL cells. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Figure 3. Loss of IRF8 decreased the growth of DLBCL in vivo. Disclosures No relevant conflicts of interest to declare.

scholarly journals Role of Immunohistochemistry in Staging Diffuse Large B-cell Lymphoma (DLBCL)

2008 ◽  
Vol 56 (10) ◽  
pp. 893-900 ◽  
Author(s):  
Dipti Talaulikar ◽  
Jane Esther Dahlstrom ◽  
Bruce Shadbolt ◽  
Amy Broomfield ◽  
Anne McDonald
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cox Regression Analysis ◽  
Cell Markers ◽  
Large B Cell Lymphoma ◽  
Lymphomatous Involvement ◽  
The Impact ◽  
Large B Cell

The use of immunohistochemistry (IHC) in staging bone marrow in non-Hodgkin's lymphoma (NHL) is largely limited to ambiguous cases, particularly those with lymphoid aggregates. Its role in routine clinical practice remains unestablished. This study aimed to determine whether the routine use of IHC in diffuse large B-cell lymphoma (DLBCL) would improve the detection of lymphomatous involvement in the bone marrow. It also sought to determine the impact of IHC on predicting survival compared with routine histological diagnosis using hematoxylin and eosin (H&E), Giemsa, and reticulin staining. The bone marrow trephines of 156 histologically proven DLBCL cases were assessed on routine histology, and IHC using two T-cell markers (CD45RO and CD3), two B-cell markers (CD20 and CD79a), and κ and λ light chains. IHC detected lymphomatous involvement on an additional 11% cases compared with histology alone. Although both routine histology and IHC were good predictors of survival, IHC was better at predicting survival on stepwise multivariate Cox regression analysis. IHC performed routinely on bone marrow trephines has the ability to improve detection of occult lymphoma in experienced hands. Furthermore, it is a better predictor of survival compared with routine histological examination alone.

Characterizing Canine Lymphoma As a Potential Large Animal Model of Human Diffuse Large B-Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5193-5193 ◽  
Author(s):  
Kristy L. Richards ◽  
Alison Motsinger-Reif ◽  
Hsiao-Wei Chen ◽  
Yuri D. Fedoriw ◽  
Cheng Fan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Animal Model ◽  
B Cell ◽  
Cell Lymphoma ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Large Animal Model ◽  
Large Animal ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 5193 Diffuse large B-cell lymphoma (DLBCL) affects ∼25,000 people in the U.S. each year, and fewer than half of them are cured with standard therapy. DLBCL can be divided into two subtypes by gene expression profiling, germinal center B-cell (GCB) type and activated B-cell (ABC) type. ABC-type DLBCL patients have significantly poorer outcomes. To improve therapeutic options, better animal models that accurately mimic human DLBCL (hDLBCL) are needed. Canine DLBCL is one of the most common cancers in veterinary oncology. Similar to human DLBCL patients, dogs with lymphoma are treated with both CHOP-like regimens and autologous stem cell transplants. Morphologically, canine lymphomas are similar to hDLBCL, with shared histologic markers, such as CD20 and PAX5. With recent technologies based on knowledge of the canine genome sequence, it is now possible to evaluate dogs as a potential large-animal model for hDLBCL. We evaluated 58 canine B-cell lymphomas by generating comprehensive gene expression profiles and comparing them to previously published hDLBCL expression profiles. Canine B-cell lymphoma expression profiles were similar in some ways to hDLBCLs. For instance, increased expression of NF-kB pathway genes was noted in a subset of lymphomas, mirroring NF-kB pathway activation in human ABC-type DLBCL. Furthermore, immunoglobulin heavy chain (IGH) mutation status, which is correlated with ABC/GCB cell of origin in hDLBCL, separated canine DLBCL into two groups with statistically different progression-free and overall survival times. However, canine DLBCL differed from hDLBCL in other aspects, including rare immunohistochemical positivity for BCL6 and MUM1/IRF4. Collectively, these results define aspects of canine B-cell lymphomas that resemble hDLBCL, identifying molecular similarities that could allow dogs to be used as a representative model of hDLBCL. Further comparative studies, including therapeutic trials, could potentially improve outcomes in both species. Disclosures: No relevant conflicts of interest to declare.

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