Molecular basis of mantle cell lymphoma

Bertoni, Francesco; Zucca, Emanuele; Cotter, Finbarr E.

doi:10.1046/j.1365-2141.2003.04761.x

Cited by 91 publications

(61 citation statements)

References 100 publications

(121 reference statements)

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“…[2][3][4] The understanding of MCL biology has been advanced considerably in recent years. 5 Although earlier studies using transgenic mice failed to show that cyclin D1 overexpression is oncogenic, 6,7 a recent study has shown that nuclear retention of cyclin D1 is oncogenic. 8 Nevertheless, better biological understanding of MCL has not yet been translated into improved clinical outcome.…”

mentioning

confidence: 99%

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Peponi

Δράκος

Reyes

et al. 2006

The American Journal of Pathology

111

108

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Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473 p-AKT, 13 of 21 (62%) Ser2448 p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

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mentioning

confidence: 99%

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Peponi

Δράκος

Reyes

et al. 2006

The American Journal of Pathology

111

108

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“…The t (11;14) determines the deregulated expression of cyclin D1 in lymphoid cells because of its proximity to B-cell immunoglobulin heavy chain transcription enhancers. 38 Two other types of cyclin D proteins, D2 and D3, also exist, and each is specific to certain tissues. Cyclins D2 and D3 are used in normal lymphoid cells, but are replaced by overexpressed cyclin D1 in cases of MCL.…”

Section: Deregulation Of Proteins Downstream Of Mtormentioning

confidence: 99%

“…The result of mTORactivated translation of mRNA is the production of proteins that are necessary for G1 cell-cycle progression and initiation of the S phase. 38 Passage from G1 to S phase is considered the most crucial step in the cell cycle.…”

Section: Relapsed or Refractory MCLmentioning

confidence: 99%

Temsirolimus in the treatment of relapsed or refractory mantle cell lymphoma

Samad¹,

Younes

2010

OTT

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Mantle cell lymphoma (MCL) is a rare and aggressive subtype of lymphoma associated with a poor prognosis. Chemotherapy is the mainstay of frontline treatment for patients with this disease. Despite high response rates to combination chemotherapy regimens, the majority of patients relapse within a few years of treatment. Therefore, finding efficacious treatments for relapsed or refractory disease has become a growing area of clinical research. The mammalian target of rapamycin (mTOR) is responsible for integrating cell signals from growth factors, hormones, and nutrients and communicating energy status. Scientific research on aberrant molecular pathways in cancer has revealed that several proteins along the mTOR pathway may be upregulated in this and other types of lymphoma. Temsirolimus is the first mTOR inhibitor that has shown clinical efficacy in treating MCL that has relapsed after frontline treatments.

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“…This property renders mTOR inhibitors particularly interesting for the treatment of MCL, because the distinguishing t(11;14) chromosomal translocation of MCL juxtaposes the cyclin D1 gene of chromosome 11 to the immunoglobulin heavy chain enhancer region of chromosome 14, and the activation of the translation process results in the overexpression of cyclin D1. As a consequence of the inhibition of mTOR, the levels of cyclin D1 and of cyclin/cyclin-dependent kinases decrease with cell-cycle arrest in G 1 [47][48][49].…”

Section: Mammalian Target Of Rapamycin Inhibitorsmentioning

confidence: 99%

Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin’s Lymphomas

2009

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1. Utilize new therapeutic agents with proven efficacy in the chemotherapy-and monoclonal antibody-refractory NHL setting.2. Analyze the study of these new agents in lymphoma subtypes and in relation to genetic aberrations of the lymphoma.3. Differentiate the toxicity of these new agents from that of chemotherapy.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTThe availability of active monoclonal antibodies, either as single agents or in combination with cytotoxic agents, has improved treatment results in non-Hodgkin's lymphoma (NHL). Despite this and the increasing number of available active monoclonal antibodies, alone or conjugated with radioisotopes, not all types of lymphoma are sensitive to these biological agents and often they become resistant because of different molecular mechanisms.New molecular targets in neoplastic cells are emerging and provide the rationale for novel discovery initiatives. In fact, a greater knowledge of the biology of lymphoma and the identification of compounds selectively active against a potential therapeutic pathway have already improved the time to progression and survival time of patients with some subtypes of NHL. The growing list of new drugs provides the exciting prospect of developing disease-specific and even patient-specific therapies.The aim of this review is to identify and discuss nonmonoclonal antibody new therapeutic agents in terms of mechanism of action and clinical results. The preclinical and clinical features of proteasome inhibitors, histone deacetylase inhibitors, thalidomide and lenalidomide,

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Molecular basis of mantle cell lymphoma

Cited by 91 publications

References 100 publications

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Temsirolimus in the treatment of relapsed or refractory mantle cell lymphoma

Beyond Monoclonal Antibodies: New Therapeutic Agents in Non-Hodgkin’s Lymphomas

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