Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Sebestyén, Anna; Sticz, T.; Márk, Ágnes; Hajdú, Melinda; Tímár, Botond; Nemes, Karolina; Nagy, Noémi; Váradi, Zsófia; Kopper, László

doi:10.1038/modpathol.2012.141

Cited by 23 publications

(28 citation statements)

References 26 publications

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“…Activation of the mTOR pathway has been shown previously in DLBCL, although not in the cell lines used herein, and a recent study has also reported activation of mTOR in a subset of DLCBL patients. 36 Moreover, eIF4B was present on two lists of genes whose expression changed following mTOR inhibition. 37, 38 Therefore, DLBCL and control cells were immunoblotted to assess the expression and phosphorylation status of protein kinase B/AKT, mTOR and 4EBP1.…”

Section: Resultsmentioning

confidence: 99%

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma

et al. 2013

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Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5′-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.

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Section: Resultsmentioning

confidence: 99%

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma

et al. 2013

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“…Studies examining the role of mTOR partners', raptor and rictor, in predicting responders are planned for the future. 11 Clinical studies are also underway evaluating mTOR-directed therapy earlier in the course of this disease and in combination with additional agents to overcome resistance thought to occur through escape via the AKT pathway. These studies are likely to identify responders to this therapy and to improve outcomes for patients with resistant DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma

et al. 2012

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Diffuse large B-cell lymphoma is an aggressive non-Hodgkin's lymphoma without a standard therapy for patients who relapse after or are not eligible for salvage autologous stem cell transplantation. In vitro analysis of lymphoma cell lines has shown that everolimus can inhibit cell cycle progression in vitro and inhibitors of the mammalian target of rapamycin have already demonstrated single-agent activity in relapsed non-Hodgkin's lymphomas including diffuse large B-cell lymphoma, validating mammalian target of rapamycin as a viable therapeutic target. We performed an open label phase II study of everolimus, an inhibitor of mammalian target of rapamycin, in combination with rituximab to examine efficacy and tolerability in patients with relapsed/refractory diffuse large B-cell lymphoma. Eligible patients were treated with everolimus 10 mg by mouth once daily on days 1-28 of a 28-day cycle with rituximab administered weekly during cycle one and then on day one of subsequent cycles. Patients were treated for a total of 12 cycles or until disease progression. The primary end-point was objective response rate, with secondary end-points being toxicity, progression-free survival, duration of response, and overall survival. Twenty-six patients (24 evaluable) were enrolled and had an overall response rate of 38% [90% CI (21%-56%)] with three complete responses and six partial responses among these 24 patients. The median duration of response among responders was 8.1 months. At a median follow-up of 12 months, the overall survival rate was 37% [90% CI (20%-54%)]. The most common grade 3 to 4 toxicities were neutropenia, anemia, and thrombocytopenia. In conclusion, everolimus in combination with rituximab is well tolerated and demonstrates activity in relapsed diffuse large B-cell lymphoma. Further studies of this combination are warranted. Clinicaltrials.gov identifier: NCT00869999

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“…We suggest that patients with poor prognosis may be identified by measuring p-4EBP1 levels at diagnosis; further markers will be required for predicting the potential response to rapamycin treatment for individual patients within this group. Indeed, it must be kept in mind that high basal mTORC1 activity does not necessarily mean that the patient will respond to MTIs [45]. Our results demonstrate that in vitro rapamycin treatment does not necessarily result in the decrease of mTOR activity in ALL cells in all cases.…”

Section: Discussionmentioning

confidence: 72%

Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

et al. 2013

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Modern treatment strategies have improved the prognosis of childhood ALL; however, treatment still fails in 25–30% of patients. Further improvement of treatment may depend on the development of targeted therapies. mTOR kinase, a central mediator of several signaling pathways, has recently attracted remarkable attention as a potential target in pediatric ALL. However, limited data exists about the activity of mTOR. In the present study, the amount of mTOR activity dependent phospho-proteins was characterized by ELISA in human leukemia cell lines and in lymphoblasts from childhood ALL patients (n = 49). Expression was measured before and during chemotherapy and at relapses. Leukemia cell lines exhibited increased mTOR activity, indicated by phospho-S6 ribosomal protein (p-S6) and phosphorylated eukaryotic initiation factor 4E binding protein (p-4EBP1). Elevated p-4EBP1 protein levels were detected in ALL samples at diagnosis; efficacy of chemotherapy was followed by the decrease of mTOR activity dependent protein phosphorylation. Optical density (OD) for p-4EBP1 (ELISA) was significantly higher in patients with poor prognosis at diagnosis, and in the samples of relapsed patients. Our results suggest that measuring mTOR activity related phospho-proteins such as p-4EBP1 by ELISA may help to identify patients with poor prognosis before treatment, and to detect early relapses. Determining mTOR activity in leukemic cells may also be a useful tool for selecting patients who may benefit from future mTOR inhibitor treatments.

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Activity and complexes of mTOR in diffuse large B-cell lymphomas—a tissue microarray study

Cited by 23 publications

References 26 publications

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma

Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma

Mammalian Target of Rapamycin (mTOR) Activity Dependent Phospho-Protein Expression in Childhood Acute Lymphoblastic Leukemia (ALL)

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