scholarly journals MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma

2019 ◽  
Vol 3 (7) ◽  
pp. 1185-1196 ◽  
Author(s):  
Hanne Due ◽  
Anna Amanda Schönherz ◽  
Laura Ryø ◽  
Maria Nascimento Primo ◽  
Ditte Starberg Jespersen ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response To Therapy ◽  
Expression Level ◽  
Outcome Analysis ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract A major clinical challenge of diffuse large B-cell lymphoma (DLBCL) is that up to 40% of patients have refractory disease or relapse after initial response to therapy as a result of drug-specific molecular resistance. The purpose of the present study was to investigate microRNA (miRNA) involvement in vincristine resistance in DLBCL, which was pursued by functional in vitro analysis in DLBCL cell lines and by outcome analysis of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Differential miRNA expression analysis identified miR-155 as highly expressed in vincristine-sensitive DLBCL cell lines compared with resistant ones. Ectopic upregulation of miR-155 sensitized germinal-center B-cell-like (GCB)–DLBCL cell lines to vincristine, and consistently, reduction and knockout of miR-155 induced vincristine resistance, documenting that miR-155 functionally induces vincristine sensitivity. Target gene analysis identified miR-155 as inversely correlated with Wee1, supporting Wee1 as a target of miR-155 in DLBCL. Chemical inhibition of Wee1 sensitized GCB cells to vincristine, suggesting that miR-155 controls vincristine response through Wee1. Outcome analysis in clinical cohorts of DLBCL revealed that high miR-155 expression level was significantly associated with superior survival for R-CHOP-treated patients of the GCB subclass, independent of international prognostic index, challenging the commonly accepted perception of miR-155 as an oncomiR. However, miR-155 did not provide prognostic information when analyzing the entire DLBCL cohort or activated B-cell–like classified patients. In conclusion, we experimentally confirmed a direct link between high miR-155 expression and vincristine sensitivity in DLBCL and documented an improved clinical outcome of GCB-classified patients with high miR-155 expression level.

scholarly journals HDAC Inhibition Effectively Induce Apoptosis in Diffuse Large B Cell Lymphoma with High Bfl-1

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4320-4320
Author(s):  
Eunchae Park ◽  
Chansub Lee ◽  
Jihyun Park ◽  
Jun Liu ◽  
Junshik Hong ◽  
...  
Keyword(s):  
Western Blot ◽  
B Cell ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Expression Level ◽  
Apoptosis Rate ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Venetoclax, a Bcl-2 specific inhibitor, shows potential benefit in certain patients with diffuse large B cell lymphoma (DLBCL) when combined with conventional cytotoxic chemotherapy. However, both de novo and acquired resistance to venetoclax is frequently observed in DLBCL and endogenous Bfl-1 expression can render DLBCL insensitive to venetoclax. Given the difficulties for direct inhibition of Bfl-1, we looked for the indirect inhibitory strategies for Bfl-1 at both transcriptional and post-translational levels. Accordingly, we decided to use a pan-histone deacetylase (HDAC) inhibitor to decrease a Bfl-1 transcriptional factor, Wilms' tumor-1 (Wt-1), while increasing Noxa, an inactivating Bfl-1 binding partner in DLBCL. We screened the expression levels of Bcl-2 family in 6 DLBCL cell lines (SUDHL-2, OCI-LY-3, TMD-8, RC-K8, OCI-LY-1, and OCI-LY-19) and divided them into 2 groups based on Bfl-1 expression level (Bfl-1+/Bfl-1-). Bfl-1+ group cell lines (SUDHL-2, OCI-LY-3, TMD-8, RC-K8) exhibited reduced sensitivity to venetoclax compared to Bfl-1- group cell lines (OCI-LY-1, OCI-LY-19) as expected. In contrast, the cell lines in Bfl-1+ group were more sensitive to panobinostat, a representative pan-HDAC inhibitor, than Bfl-1- group cell lines. We could also validate the association between Bfl-1 expression and panobinostat response using 12 DLBCL cell lines data from Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC). With western blot, we confirmed that as the concentration of panobinostat increases, Bfl-1 and Wt-1 were decreased and Noxa was increased as we hypothesized. In a time-course analysis, Bfl-1 was downregulated by panobinostat in a Wt-1, and Noxa-dependent manner. Additionally, we confirmed that the association of Bfl-1 with venetoclax and panobinostat was linked to apoptosis rate using Western blot and Flow cytometry. Finally, to evaluate the impact of Bfl-1 on the vulnerability of cells to panobinostat, we compared the sensitivity to panobinostat upon shRNA-mediated Bfl-1 knockdown using SUDHL-2 cells (the strongest Bfl-1 expression level among DLBCL cell lines). Reduced sensitivity was observed in Bfl-1 knocked down cells comparing to Non-Infected (NI) and scrambled vector transduced cells. Apoptosis rate was decreased significantly in Bfl-1 knocked down cells as well. Therefore, we identified the sensitivity to panobinostat depends on the expression of Bfl-1 in DLBCL. In summary, we identified the significance of Bfl-1 on HDAC inhibitor response and confirmed that Wt-1 and Noxa play important roles in that process. Our results provide a mechanistic rationale for utilizing HDAC inhibitors for DLBCL patients using Bfl-1 as a prediction marker. Accordingly, HDAC inhibitor can be therapeutic options for some DLBCL patients with high Bfl-1. Disclosures Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria.

scholarly journals The Adhesion Molecule ICAM-1 in Diffuse Large B-Cell Lymphoma Post-Rituximab Era: Relationship with Prognostic Importance and Rituximab Resistance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4212-4212
Author(s):  
Qunling Zhang ◽  
Juan J Gu ◽  
Cory Mavis ◽  
Ye Guo ◽  
Matthew J. Barth ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Adhesion Molecule ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
The Other ◽  
Expression Level ◽  
Chop Chemotherapy ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface receptor involving in cell-to-cell adhesion and as well as co-stimulatory molecule involved in T-cell lymphocyte infiltration and activation. In the pre-rituximab era, high level of ICAM-1 was reported to be a prognostic indicator of better clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The value of ICAM-1 expression in the post-rituximab era remains unclear. To investigate the impact of ICAM-1 expression in DLBCL, we conducted a retrospective study in R+CHOP treated patients. Methods: Patients (N=102) with histologically proven DLBCL treated at Fudan University Shanghai Cancer Center with available diagnostic biopsy material were identified. Forty-three patients were treated with CHOP and 59 patients with R+CHOP. ICAM-1 expression was determined by immunohistochemistry (IHC). ICAM-1 expression was quantified by staining intensity or percentage of positive cells. Tumors were considered positive when at least 75% of tumor cells expressed ICAM-1. Progression free survival (PFS) and overall survival (OS) was plotted by Kaplan-Meier method and curves were compared with the long-rank test in both groups. Correlation between the ICAM-1 expression and clinical variables were tested by Pearson Chi Square test and a two-sided P value of <0.05 was considered to be statistically significant. Finally, ICAM-1 expression was determined in a panel of rituximab-sensitive (RSCL) and rituximab-resistant lymphoma cell lines (RRCL) by western blot. Correlation of ICAM-1 expression and rituximab anti-tumor activity was determined by standard complement-mediated cytotoxicity (CMC) and antibody-dependent cellular cytotoxicity (ADCC) assays. Result: ICAM-1 expressionwas detected in 28 (27.5%) DLBCL patients. The rest of the patients tested negative for ICAM-1 (N=74; 72.5%). Differences in ICAM-1 expression were observed according to cell of origin DLBCL subtype. ICAM-1 expression was higher among germinal center B-cell (GCB) DLBCL (41.4%) vs. non-GCB subtype patients (19.6%, P=0.019). The response rates for R-CHOP and CHOP were, respectively, 89.4% and 77.7% (P=0.409) in ICAM-1 positive patients and 92.5% and 73.5% (p=0.027) in ICAM-1 negative patients. As previously described, ICAM-1 expression was associated with an improved PFS/OS (P=0.03/ P=0.05) in CHOP-treated DLBCL. On the other hand, no differences in PFS/OS were observed between ICAM-1 positive or negative DLBCL patients treated with R+CHOP. The addition of rituximab to CHOP chemotherapy resulted in an improved PFS in ICAM-1 negative DLBCL (P=0.018). On the other hand, the clinical outcome of ICAM-1 positive DLBCL patients treated with CHOP chemotherapy was similar than R+CHOP treated patients. Finally, loss of ICAM-1 expression level was found in our rituximab resistant cell lines, along with reduction of rituximab activity. Conclusion: Before therituximab era, ICAM-1 low expression correlated with worse PFS and OS. In our retrospective clinical analysis, we found that rituximab significantly improved the overall response rate and PFS in ICAM-1 negative subset patients. Our data also indicated that ICAM-1 expression level was higher in GCB than non-GCB subtypes, and this may contribute to better rituximab response in GCB cell types. Gradually exposed lymphoma cell to rituximab lost ICAM-1 expression and may contribute to the resistance to rituximab and chemotherapy agents. Further investigation of ICAM-1 expression needed to be study to enhance the rituximab therapy in lymphoma. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals MicroRNA-181a Inhibits Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Progression by Repressing CARD11

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Danxia Zhu ◽  
Cheng Fang ◽  
Wenting He ◽  
Chen Wu ◽  
Xiaodong Li ◽  
...  
Keyword(s):  
B Cell ◽  
Binding Site ◽  
Cell Lines ◽  
Expression Vector ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Wild Type ◽  
Protein Levels ◽  
Large B Cell Lymphoma ◽  
Large B Cell

We investigated the role of miR-181a in diffuse large B-cell lymphoma (DLBCL) and its potential target genes. miR-181a levels were lower in activated B-cell- (ABC-) like DLBCL cells than that in germinal center B-cell- (GCB-) like DLBCL cells. Overexpression of miR-181a in ABC-like DLBCL cell lines (OCI-LY10 and U2932) resulted in G0/G1 cell cycle arrest, increased apoptosis, and decreased invasiveness. miRNA target prediction programs (miRanda, TargetScan, and miRDB) identified caspase recruitment domain-containing protein 11 (CARD11) as a putative miR-181a target. CARD11 mRNA and protein levels were higher in the ABC-like DLBCL than that in GCB-like DLBCL. Moreover, CARD11 mRNA and protein levels were downregulated in the OCI-LY10 and U2932 cell lines overexpressing miR-181a. Dual luciferase reporter assays confirmed the miR-181a binding site in the CARD11 3′UTR region. OCI-LY10 and U2932 cells transfected with a CARD11 expression vector encoding miR-181a with a mutated binding site showed higher CARD11 protein levels, cell viability, G2/M phase cells, and invasiveness compared to those transfected with a wild-type CARD11 expression vector. Nude mice xenografted with OCI-LY10 cells with overexpressed wild-type miR-181a generated smaller tumors compared to those with overexpressed mutated binding site of CARD11 3′UTR and miR-181a. These results indicate that miR-181a inhibits ABC-like DLBCL by repressing CARD11.

scholarly journals Concomitant statin use does not impair the clinical outcome of patients with diffuse large B cell lymphoma treated with rituximab-CHOP

2010 ◽  
Vol 89 (8) ◽  
pp. 783-787 ◽  
Author(s):  
Panagiotis Samaras ◽  
Helen Heider ◽  
Sarah R. Haile ◽  
Ulf Petrausch ◽  
Niklaus G. Schaefer ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Statin Use

Serum soluble Fas level determines clinical outcome of patients with diffuse large B-cell lymphoma treated with CHOP and R-CHOP

2009 ◽  
Vol 135 (10) ◽  
pp. 1421-1428 ◽  
Author(s):  
Takeshi Hara ◽  
Hisashi Tsurumi ◽  
Naoe Goto ◽  
Nobuhiro Kanemura ◽  
Takeshi Yoshikawa ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Soluble Fas ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Repurposing dasatinib for diffuse large B cell lymphoma

2019 ◽  
Vol 116 (34) ◽  
pp. 16981-16986 ◽  
Author(s):  
Claudio Scuoppo ◽  
Jiguang Wang ◽  
Mirjana Persaud ◽  
Sandeep K. Mittan ◽  
Katia Basso ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Kinase Inhibitor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Multikinase Inhibitor ◽  
Large B Cell Lymphoma ◽  
Large B Cell

To repurpose compounds for diffuse large B cell lymphoma (DLBCL), we screened a library of drugs and other targeted compounds approved by the US Food and Drug Administration on 9 cell lines and validated the results on a panel of 32 genetically characterized DLBCL cell lines. Dasatinib, a multikinase inhibitor, was effective against 50% of DLBCL cell lines, as well as against in vivo xenografts. Dasatinib was more broadly active than the Bruton kinase inhibitor ibrutinib and overcame ibrutinib resistance. Tumors exhibiting dasatinib resistance were commonly characterized by activation of the PI3K pathway and loss of PTEN expression as a specific biomarker. PI3K suppression by mTORC2 inhibition synergized with dasatinib and abolished resistance in vitro and in vivo. These results provide a proof of concept for the repurposing approach in DLBCL, and point to dasatinib as an attractive strategy for further clinical development in lymphomas.

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