The Expression and Effect of B7-H3 in Mantle Cell Lymphoma

Abstract Objective : To investigate the effects of B7-H3 (CD276) on oncogenesis and chemosensitivity in mantle cell lymphoma (MCL). Methods : The B7-H3 expression was detected by flow cytometry in cell lines, 20 patients with MCL and 20 volunteers. B7-H3 knockdown was performed using lentivirus transduction in the Maver and Z138 mantle cell lymphoma cell lines, respectively. The effects of B7-H3 on cell proliferation, cycle, migration and invasion were investigated by CCK-8 assay, methyl cellulose colony forming assay, PI staining, and Transwell assays in vitro. By establishing Maver and Z138 xenograft models, the effects of B7-H3 on tumourigenicity were observed, and Ki-67 and PCNA was detected through immunohistochemical. Moreover, the impacts of B7-H3 RNAi on the anti-tumor effect of chemotherapy drugs were determined with CCK-8, Annexin V-FITC/PI and Hoechst 33342 staining assays in vitro and with xenograft models in vivo. Results: The frequency of B7-H3positive expression cases was 65.0% (13/20) in MCL patients and 10.0% (2/20) in volunteers. The down-regulation of B7-H3 significantly decreased tumor proliferation in MCL in vitro and in vivo. In the B7-H3 knockdown groups of Maver and Z138 xenograft models, the mean inhibition rate of tumor growth was 59.1% and 65.0% (p = 0.010 and 0.003), and the expression of both Ki-67 and PCNA were significantly lower, respectively. After B7-H3 silencing, the cell cycles of Maver and Z138 were both arrested at G0/G1 phase, and the expression of cell cycle-related proteins Cyclin D1 and CDK4 was lower. The cell migration rates and invasion capacity were decreased, and the rates of distant metastasis in B7-H3 knockdown both Maver and Z138 xenografts were significantly declined as well. The expression of invasion-related proteins MMP-2 and MMP-9 was lower in B7-H3 knockdown cells and xenografts. The silencing of B7-H3 increased the sensitivity of Maver and Z138 cells to Rituximab and Bendamustine and enhanced the drug-induced apoptosis, respectively. The activity of caspase-3 in vitro and the expression of caspase-3 in both Maver and Z138 xenografts was significantly increased in the B7-H3 shRNA combined with chemotherapy drugs groups. Conclusions: B7-H3 levels in MCL patients were signifiantly higher than that in volunteers. Our study demonstrates for the first time that B7-H3 promotes mantle cell lymphoma progression and B7-H3 knockdown significantly enhances the chemosensitivity. This may provide a new therapeutic approach to mantle cell lymphoma. Disclosures No relevant conflicts of interest to declare.

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Atiprimod inhibits the growth of mantle cell lymphoma in vitro and in vivo and induces apoptosis via activating the mitochondrial pathways

Blood ◽

10.1182/blood-2006-12-063958 ◽

2007 ◽

Vol 109 (12) ◽

pp. 5455-5462 ◽

Cited By ~ 30

Author(s):

Michael Wang ◽

Liang Zhang ◽

Xiaohong Han ◽

Jing Yang ◽

Jianfei Qian ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Apoptosis ◽

Caspase 3 ◽

Cell Lymphoma ◽

Caspase 9 ◽

Mantle Cell ◽

Induced Apoptosis ◽

Apoptosis Inducing Factor

Abstract Atiprimod is a novel cationic amphiphilic compound and has been shown to exert antimyeloma effects both in vitro and in mouse experiments. This study was undertaken to evaluate the therapeutic efficacy of atiprimod on mantle cell lymphoma (MCL) and elucidate the mechanism by which it induces cell apoptosis. Atiprimod inhibited the growth and induced apoptosis of MCL cell lines and freshly isolated primary tumor cells in vitro. More importantly, atiprimod significantly inhibited tumor growth in vivo and prolonged the survival of tumor-bearing mice. However, atiprimod also exhibited lower cytotoxicity toward normal lymphocytes. Atiprimod activated c-Jun N-terminal protein kinases (JNK) and up-regulated the level of Bax, Bad, and phosphorylated Bcl-2, resulting in release of apoptosis-inducing factor (AIF) and cytochrome c from mitochondria and activation and cleavage of caspase-9, caspase-3, and PARP. However, AIF, but not activation of caspases or PARP, was responsible for apoptosis in MCL cells because an AIF inhibitor, but not pan-caspase or paspase-9 inhibitors, completely abrogated atiprimod-induced apoptosis. Taken together, our results demonstrate that atiprimod displays a strong anti-MCL activity. Cell apoptosis was induced mainly via activation of the AIF pathway. These results support the use of atiprimod as a potential agent in MCL chemotherapy.

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Role of the microenvironment in mantle cell lymphoma: IL-6 is an important survival factor for the tumor cells

Blood ◽

10.1182/blood-2012-04-424630 ◽

2012 ◽

Vol 120 (18) ◽

pp. 3783-3792 ◽

Cited By ~ 74

Author(s):

Liang Zhang ◽

Jing Yang ◽

Jianfei Qian ◽

Haiyan Li ◽

Jorge E. Romaguera ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Drug Induced ◽

Growth And Survival ◽

Chemotherapy Drugs ◽

Non Hodgkin Lymphoma ◽

Mantle Cell

Abstract Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma frequently involved in the lymph nodes, bone marrow, spleen, and gastrointestinal tract. We examined the role of IL-6 in MCL. Human MCL cells expressed the membrane gp130 and soluble gp80, and some of them also secreted IL-6. Neutralizing autocrine IL-6 and/or blocking IL-6 receptors in IL-6+/gp80+ MCL cells inhibited cell growth, enhanced the rate of spontaneous apoptosis, and increased sensitivity to chemotherapy drugs. For IL-6− or gp80low MCL cells, paracrine or exogenous IL-6 or gp80 protected the cells from stress-induced death. Knockdown of gp80 in gp80high MCL cells rendered the cells more sensitive to chemotherapy drugs, even in the presence of exogenous IL-6. In contrast, overexpression of gp80 in gp80low/IL-6+ MCL cells protected the cells from chemotherapy drug-induced apoptosis in vitro and compromised the therapeutic effect of chemotherapy in vivo. IL-6 activated the Jak2/STAT3 and PI3K/Akt pathways in MCL, and the inhibition of these pathways completely or partially abrogated IL-6–mediated protection of MCL cells. Hence, our study identifies IL-6 as a key cytokine for MCL growth and survival and suggests that targeting the IL-6 pathway may be a novel way to improve the efficacy of chemotherapy in MCL patients.

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P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines

Molecular Cancer ◽

10.1186/1476-4598-11-77 ◽

2012 ◽

Vol 11 (1) ◽

pp. 77 ◽

Cited By ~ 14

Author(s):

Nitesh P Shirsath ◽

Sonal M Manohar ◽

Kalpana S Joshi

Keyword(s):

Cell Cycle ◽

Mantle Cell Lymphoma ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Cyclin Dependent Kinase ◽

Cyclin Dependent Kinase Inhibitor ◽

Mantle Cell Lymphoma Cell ◽

Mantle Cell

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BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

ESMO Open ◽

10.1136/esmoopen-2018-000387 ◽

2018 ◽

Vol 3 (6) ◽

pp. e000387 ◽

Cited By ~ 10

Author(s):

Chiara Tarantelli ◽

Elena Bernasconi ◽

Eugenio Gaudio ◽

Luciano Cascione ◽

Valentina Restelli ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Antitumour Activity ◽

Single Agent ◽

Treatment Strategies ◽

Bet Inhibitor ◽

Mantle Cell

BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.Materials and methodsThe activity of birabresib as a single agent and in combination, as well as its mechanism of action was studied in MCL cell lines.ResultsBirabresib showed in vitro and in vivo activities, which appeared mediated via downregulation of MYC targets, cell cycle and NFKB pathway genes and were independent of direct downregulation of CCND1. Additionally, the combination of birabresib with other targeted agents (especially pomalidomide, or inhibitors of BTK, mTOR and ATR) was beneficial in MCL cell lines.ConclusionOur data provide the rationale to evaluate birabresib in patients affected by MCL.

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Ofatumumab Exhibits Enhanced In Vitro and In Vivo Activity Compared to Rituximab in Preclinical Models of Mantle Cell Lymphoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-15-0056 ◽

2015 ◽

Vol 21 (19) ◽

pp. 4391-4397 ◽

Cited By ~ 18

Author(s):

Matthew J. Barth ◽

Cory Mavis ◽

Myron S. Czuczman ◽

Francisco J. Hernandez-Ilizaliturri

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Preclinical Models ◽

Mantle Cell

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Antitumoral Activity of Lenalidomide in In Vitro and In Vivo Models of Mantle Cell Lymphoma Involves the Destabilization of Cyclin D1/p27KIP1 Complexes

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-13-1569 ◽

2013 ◽

Vol 20 (2) ◽

pp. 393-403 ◽

Cited By ~ 16

Author(s):

Alexandra Moros ◽

Sophie Bustany ◽

Julie Cahu ◽

Ifigènia Saborit-Villarroya ◽

Antonio Martínez ◽

...

Keyword(s):

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Antitumoral Activity ◽

In Vivo Models ◽

Mantle Cell

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HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma

Blood ◽

10.1182/blood-2016-04-711176 ◽

2016 ◽

Vol 128 (21) ◽

pp. 2517-2526 ◽

Cited By ~ 19

Author(s):

Caron Jacobson ◽

Nadja Kopp ◽

Jacob V. Layer ◽

Robert A. Redd ◽

Sebastian Tschuri ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Hsp90 Inhibitors ◽

Hsp90 Inhibition ◽

Key Points ◽

Mantle Cell ◽

Ibrutinib Resistance

Key Points Inhibition of HSP90 targets multiple dependences in mantle cell lymphoma. Clinically available HSP90 inhibitors overcome ibrutinib resistance in vitro and in vivo.

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ROR1-targeted delivery of OSU-2S, a nonimmunosuppressive FTY720 derivative, exerts potent cytotoxicity in mantle-cell lymphoma in vitro and in vivo

Experimental Hematology ◽

10.1016/j.exphem.2015.04.008 ◽

2015 ◽

Vol 43 (9) ◽

pp. 770-774.e2 ◽

Cited By ~ 10

Author(s):

Rajeswaran Mani ◽

Chi-Ling Chiang ◽

Frank W. Frissora ◽

Ribai Yan ◽

Xiaokui Mo ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Targeted Delivery ◽

Cell Lymphoma ◽

Mantle Cell

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GST-n and Nitric Oxide: A Novel Approach to Mantle Cell Lymphoma Therapy.

Blood ◽

10.1182/blood.v114.22.3729.3729 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3729-3729

Author(s):

Heather Gilbert ◽

John Cumming ◽

Josef T. Prchal ◽

Michelle Kinsey ◽

Paul Shami

Keyword(s):

Nitric Oxide ◽

Mantle Cell Lymphoma ◽

Cell Lines ◽

Cell Lymphoma ◽

Xenograft Model ◽

Malignant Cells ◽

Mantle Cell ◽

Tumor Viability

Abstract Abstract 3729 Poster Board III-665 Mantle cell lymphoma (MCL) is a well defined B-cell non-Hodgkin lymphoma characterized by a translocation that juxtaposes the BCL1 gene on chromosome 11q13, which encodes cyclin D1 (CD1), next to the immunoglobulin heavy chain gene promoter on chromosome 14. The resulting constitutive overexpression of CD1 leads to a deregulated cell cycle and activation of cell survival mechanisms. In addition, the gene which encodes GST-n, an enzyme that has been implicated in the development of cancer resistance to chemotherapy, is also located on chromosome 11q13 and is often coamplified along with the BCL1 gene in MCL (1). These two unique biological features of MCL - the overproduction of cyclin D1 and GST-n – may be involved in the carcinogenesis, tumor growth and poor response of this disease to treatment, and they offer potential mechanisms for targeted anti-cancer therapy. Nitric oxide (NO) is a biologic effector molecule that contributes to a host's immune defense against microbial and tumor cell growth. Indeed, NO is potently cytotoxic to tumor cells in vitro (2–4). However, NO is also a potent vasodilator and induces hypotension, making the in vivo administration of NO very difficult. To use NO in vivo requires agents that selectively deliver NO to the targeted malignant cells. A new compound has recently been developed that releases NO upon interaction with glutathione in a reaction catalyzed by GST-n. JS-K seeks to exploit known GST-n upregulation in malignant cells by generating NO directly in cancer cells, and it has been shown to decrease the growth and increase apoptosis in vitro in AML cell lines, AML cells freshly isolated from patients, multiple myeloma cell lines, hepatoma cells and prostate cancer cell lines (3, 5–7). JS-K also decreases tumor burden in NOD/SCID mice xenografted with AML and multiple myeloma cells (5, 7). Importantly, JS-K has been used in cytotoxic doses in the mouse model without significant hypotension. To evaluate whether JS-K treatment has anti-tumor activity in MCL, the human MCL cell lines Jeko1, Mino, Granta and Hb-12 were grown with media only, with JS-K at varying concentrations and with DMSO as an appropriate vehicle control. For detection of apoptotic cells, cell-surface staining was performed with FITC-labeled anti–Annexin V and PI. Cell growth was evaluated using the Promega MTS cytotoxicity assay. Results show that JS-K (at concentrations up to 10 μM) inhibits the growth of MCL lines compared to untreated controls, with an average IC50 of 1 μM. At 48 hours of incubation, all cell lines showed a significantly greater rate of apoptosis than untreated controls. A human MCL xenograft model was then created by subcutaneously injecting two NOD/SCID IL2Rnnull mice with luciferase-transfected Hb12 cells. Seven days post-injection, one of the mice was treated with JS-K at a dose of 4 μmol/kg (expected to give peak blood levels of around 17 mM in a 20 g mouse). Injections of JS-K were given intravenously through the lateral tail vein 3 times a week. The control mouse was injected with an equivalent volume of micellar formulation (vehicle) without active drug. The Xenogen bioluminescence imaging clearly showed a difference in tumor viability, with a significantly decreased signal in the JS-K treated mouse. Our studies demonstrate that JS-K markedly decreases cell proliferation and increases apoptosis in a concentration- and time-dependent manner in mantle cells in vitro. In a xenograft model of mantle cell lymphoma, treatment with JS-K results in decreased tumor viability. Proposed future research includes further defining the molecular basis of these treatment effects; using this therapy in combination with other cancer treatments both in vitro and in vivo; and studying JS-K treatment in MCL patients. Disclosures: Shami: JSK Therapeutics: Founder, Chief Medical Officer, Stockholder.

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