scholarly journals ROR1 is Expressed in Diffuse Large B-Cell Lymphoma (DLBCL) and a Small Molecule Inhibitor of ROR1 (KAN0441571C) Induced Apoptosis of Lymphoma Cells

Biomedicines ◽  
2020 ◽  
Vol 8 (6) ◽  
pp. 170
Author(s):  
Amineh Ghaderi ◽  
Amir Hossein Daneshmanesh ◽  
Ali Moshfegh ◽  
Parviz Kokhaei ◽  
Jan Vågberg ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Small Molecule ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Induced Apoptosis ◽  
Large B Cell

The receptor tyrosine kinase ROR1 is absent in most normal adult tissues, but overexpressed in several malignancies. In this study, we explored clinical and functional inhibitory aspects of ROR1 in diffuse large B-cell lymphoma (DLBCL). ROR1 expression in tumor cells was more often observed in primary refractory DLBCL, Richter’s syndrome and transformed follicular lymphoma than in relapsed and non-relapsed DLBCL patients (p < 0.001). A survival effect of ROR1 expression was preliminarily observed in relapsed/refractory patients independent of gender and stage but not of age, cell of origin and international prognostic index. A second generation small molecule ROR1 inhibitor (KAN0441571C) induced apoptosis of ROR1+ DLBCL cell lines, similar to venetoclax (BCL-2 inhibitor) but superior to ibrutinib (BTK inhibitor). The combination of KAN0441571C and venetoclax at EC50 concentrations induced almost complete killing of DLBCL cell lines. Apoptosis was accompanied by the downregulation of BCL-2 and MCL-1 and confirmed by the cleavage of PARP and caspases 3, 8, 9. PI3Kδ/AKT/mTOR (non-canonical Wnt pathway) as well as β-catenin and CK1δ (canonical pathway) were inactivated. In zebra fishes transplanted with a ROR1+ DLBCL cell line, KAN0441571C induced a significant tumor reduction. New drugs with mechanisms of action other than those available for DLBCL are warranted. ROR1 inhibitors might represent a novel promising approach.

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 Concurrent Expression of MYC and BCL2 in Diffuse Large B-Cell Lymphoma Treated With Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone

2012 ◽  
Vol 30 (28) ◽  
pp. 3452-3459 ◽  
Author(s):  
Nathalie A. Johnson ◽  
Graham W. Slack ◽  
Kerry J. Savage ◽  
Joseph M. Connors ◽  
Susana Ben-Neriah ◽  
...  
Keyword(s):  
Protein Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
Molecular Subtype ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein ◽  
Large B Cell

Purpose Diffuse large B-cell lymphoma (DLBCL) is curable in 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MYC translocations, with or without BCL2 translocations, have been associated with inferior survival in DLBCL. We investigated whether expression of MYC protein, with or without BCL2 protein expression, could risk-stratify patients at diagnosis. Patients and Methods We determined the correlation between presence of MYC and BCL2 proteins by immunohistochemistry (IHC) with survival in two independent cohorts of patients with DLBCL treated with R-CHOP. We further determined if MYC protein expression correlated with high MYC mRNA and/or presence of MYC translocation. Results In the training cohort (n = 167), MYC and BCL2 proteins were detected in 29% and 44% of patients, respectively. Concurrent expression (MYC positive/BCL2 positive) was present in 21% of patients. MYC protein correlated with presence of high MYC mRNA and MYC translocation (both P < .001), but the latter was less frequent (both 11%). MYC protein expression was only associated with inferior overall and progression-free survival when BCL2 protein was coexpressed (P < .001). Importantly, the poor prognostic effect of MYC positive/BCL2 positive was validated in an independent cohort of 140 patients with DLBCL and remained significant (P < .05) after adjusting for presence of high-risk features in a multivariable model that included elevated international prognostic index score, activated B-cell molecular subtype, and presence of concurrent MYC and BCL2 translocations. Conclusion Assessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosis.

scholarly journals Diffuse large B-cell lymphoma: A single-institution experience of patient outcomes.

2016 ◽  
Vol 34 (7_suppl) ◽  
pp. 271-271
Author(s):  
Ryan James Chan ◽  
Rasna Gupta ◽  
Sindu Mary Kanjeekal ◽  
Mohammed Jarrar ◽  
Amin Kay ◽  
...  
Keyword(s):  
British Columbia ◽  
B Cell ◽  
Cell Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Canadian Province ◽  
Large B Cell Lymphoma ◽  
Cancer Program ◽  
Large B Cell

271 Background: The Windsor Regional Cancer Program (WRCP) was determined to have consistently been a top performer in time to treatment of diffuse large B cell lymphoma in this Canadian province (http://www.csqi.on.ca/by_type_of_cancer/lymphoma/lymphoma_treatment/). We endeavored to determine whether faster time to diagnosis and treatment for diffuse large B-cell lymphoma (DLBCL) influenced the IPI score (International Prognostic Score), thereby predicting an improved clinical outcome in these presenting patients. Methods: The WRCP services a catchment area of 650,000 people. A retrospective chart review was conducted for patients diagnosed with DLBCL at the Windsor Regional Cancer Program (WRCP) between 2006-2012. Information collected included the five factors for scoring by the International Prognostic Index (IPI) – age, performance status, LDH, stage, and number of extranodal sites – chemotherapy regimen, relapses, existence of second malignancies, cause of death, and dates of diagnosis, last follow-up, and death. We analyzed the relationship between prognostic factors and these clinical outcomes, and also compared the IPI scores for this cohort of patients against a similar population in another Canadian province, British Columbia. Results: It is established that compared to other cancer centres in Ontario, the WRCP is consistently reporting a shorter diagnosis to treatment metric when compared to their counterparts in Ontario, Canada. When compared to historical Canadian data, presenting IPI scores for DLBCL patients were lower on average for patients treated at the WRCP than those reported in British Columbia, Canada by Sehn et al. [Sehn, L. H., et al. (2007). The revised International Prognostic Index is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood, 109(5), 1857-1861.]. Conclusions: A lower presenting IPI score is known to be correlated improved lymphoma related outcome. With attention to the metric of diagnosis to treatment < 30 days for diffuse large B cell lymphoma, we expect an improved lymphoma related outcome for our patients. We recommend ongoing attention to this metric, in order to improve outcomes for our patients.

scholarly journals Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1350-1358 ◽  
Author(s):  
Ash A. Alizadeh ◽  
Andrew J. Gentles ◽  
Alvaro J. Alencar ◽  
Chih Long Liu ◽  
Holbrook E. Kohrt ◽  
...  
Keyword(s):  
B Cell ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Single Gene ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractSeveral gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the “germinal center B cell–like” subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of “cell-of-origin” classification, “stromal signatures,” IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

Sign in / Sign up

Export Citation Format

Share Document