Establishment and characterization of therapy-resistant mantle cell lymphoma cell lines derived from diff erent tissue sites

Ahrens, Adam K.; Chaturvedi, Nagendra K.; Nordgren, Tara M.; Davé, Bhavana J.; Joshi, Shantaram S.

doi:10.3109/10428194.2012.691481

Cited by 7 publications

(14 citation statements)

References 34 publications

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“…The therapy-resistant MCL cell lines were characterized and established after transplanting the Granta 519 into the NOD-SCID mice following treatment with CHOP chemotherapy and bortezomib as described previously (16, 38). These therapy-resistant tumor cells derived from liver, kidney and lungs were described as Granta 519 resistant from liver (GRL), Granta 519 resistant from kidney (GRK), and Granta 519 resistant from lungs (GRR), respectively, and compared to parental Granta 519 cells (GP).…”

Section: Methodsmentioning

confidence: 99%

“…These cells have been shown to be resistant to chemotherapy as confirmed both in vitro and in vivo studies. The additional properties of these therapy-resistant cell lines have been recently published (16, 38). …”

Section: Methodsmentioning

confidence: 99%

“…Several lines of evidence indicate that NF-κB pathway is constitutively active in MCL which leads to the overexpression of several anti-apoptotic molecules (9–15). Also, gene expression analyses of MCL patient samples and therapy-resistant MCL cells derived from different tissue sites have frequently shown high expression of NF-κB target genes (12, 16, 17). Consequently, inhibition of this constitutive activation of NF-κB has been shown to elicit cell cycle arrest and cell death in MCL cells (10, 13–15, 18).…”

Section: Introductionmentioning

confidence: 99%

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Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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Mantle cell lymphoma (MCL) is one of the most aggressive B cell non-Hodgkin lymphomas with a median survival of about five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared to control cells. Furthermore, we observed down-regulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB regulated genes such as cyclin D1, Bcl-XL and Mcl-1 were down-regulated in 13-197-treated cells. 13-197 also inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL bearing NOD-SCID mice compared to vehicle treated mice; indeed, 13-197 significantly increased the survival of MCL transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Chaturvedi

Rajule

Shukla

et al. 2013

Molecular Cancer Therapeutics

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“…The therapy-resistant MCL cell lines were established from the relapsed lymphoma cells from liver, kidney, and lungs from Granta 519 bearing NOD-SCID mice following treatment with CHOP chemotherapy and bortezomib as described previously [11,12]. These therapy-resistant tumor cells derived from liver, kidney, and lungs were described as GRL isolated from liver, GRK isolated from kidney, and GRR isolated from lungs, respectively, and compared to parental Granta 519 cells (GP).…”

Section: Generation Of Therapy-resistant MCL Cell Linesmentioning

confidence: 99%

“…As previously described, our lab has generated therapyresistant MCL cell lines from the relapsed lymphoma from liver (GRL), kidney (GRK), and lungs (GRR) of CHOP and bortezomib-treated NOD-SCID mice bearing Granta 519 human MCL [11,12]. During the characterization of these therapy-resistant MCL cell lines, gene expression profiling was done in comparison to parental Granta 519 (GP).…”

Section: Introductionmentioning

confidence: 99%

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

et al. 2013

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Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) which is one of the most aggressive lymphomas. Despite recent improvements in therapies, the development of therapy-resistance is still a major problem; therefore, in order to understand the molecular basis of therapy-resistance, stable therapy-resistant MCL cell lines have been established by us. Based on the gene expression profiles of these cell lines, Polo-like kinase 1 (PLK1) was chosen as a therapeutic target. In this paper, we demonstrate a significant antilymphoma effect of targeting PLK1 in therapy-resistant MCL cells and primary MCL cells from refractory patients. PLK1 knockdown with the antisense oligonucleotide (ASO)/or small molecule inhibitor BI2536 showed significantly decreased proliferation and increased apoptosis in therapy-resistant MCL cell lines and MCL primary cells. Additionally, the direct proteinprotein interaction partners of PLK1 were mapped using ingenuity pathway and confirmed the level of association of these partners with PLK1 based on their expression changes following PLK1 knockdown using real-time PCR. Results suggest that PLK1 is a viable target for the treatment of therapy-resistant MCL.

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Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma

et al. 2019

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Mantle cell lymphoma (MCL) is a B-cell malignancy with poor clinical outcome and undefined pathogenesis. Development of clinically relevant cellular models for MCL research is an urgent need. Our preliminary observations lead the development of two novel hypotheses that we tested in this study: 1. multicellular spheroid might be a unique growth mode of early-stage cells in MCL; 2. MCL might be a polyclonal tumor. We made the following original observations that have not been reported: First, we have provided a new experiment method for enriching MCL early-stage cells and characterized the spheroid mode of growth as a unique feature of early-stage MCL cells in cell line as well as in clinical samples. Second, we have established a clinically relevant cellular model of MCL, the JeKo-1-spheroid cell line, that was highly enriched in early-stage sub-clones. JeKo-1-spheroid cells and the spheroid growing cells enriched from MCL patients exhibited comparably enhanced tumorigenic abilities and similar biological features. Third, Immunophenotypic analysis has revealed that MCL may be derived from precursor-B(pre-B), immature-B and mature-B cells, not only the mature-B cells as WHO classified in 2016. Fourth, MCL may be a polyclonal disease composed of CD19–/IgM–, CD19–/IgM+, CD19+/IgM+ three sub-clones, of which the CD19–/IgM+ sub-clone might be the dominant sub-clone with the strongest tumorigenic ability. Fifth, CD19+/IgM– that differentiates MCL and normal B cells may represent a new marker for MCL early detection, minor residual disease monitoring after therapies and prognosis.

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Establishment and characterization of therapy-resistant mantle cell lymphoma cell lines derived from diff erent tissue sites

Cited by 7 publications

References 34 publications

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

Identification and characterization of the cellular subclones that contribute to the pathogenesis of mantle cell lymphoma

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