Expression and phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 in B-cell lymphomas and reactive lymphoid tissues.
ABSTRACT Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated.
To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues.
Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues.
Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N = 10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N = 50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous.
The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.
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ABSTRACT: Merkel cell polyomavirus (MCV) has been identified as the cause of Merkel cell carcinoma. The increased incidence of chronic lymphocytic leukemia in Merkel cell cancer cohorts and the lymphotropic properties of the virus suggest a possible viral association with lymphomagenesis. To investigate this potential role, we explored seroreactivity against MCV VP1 capsids within the Epilymph case-control study in Spain. Serum samples from 468 incident lymphomas, categorized into up to 11 entities, and 522 controls frequency matched by age, sex, and recruitment center were tested for MCV antibodies by enzyme immunoassay using Virus-Like-Particles. Adjusted multinomial logistic regression was used to estimate the OR and 95% confidence interval (CI) associated to MCV seroprevalence. Immunosuppressed subjects were excluded. MCV seroprevalence was 82% in controls and 85% in lymphoma cases. Among 11 lymphoma categories, MCV seropositivity was significantly higher in diffuse large B-cell lymphomas (DLBCL; 96.4%; OR = 6.1, 95%CI = 1.9-19.8), as compared with controls. MCV prevalences were also higher in follicular lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia, Hodgkin lymphoma, and mature T-cell lymphoma but differences did not reach statistical significance. Lower prevalences were observed for multiple myeloma and other B-cell lymphoma. Exclusion of samples collected after start of treatment did not change the results. In a subset analysis, no significant association was observed between BKV and JCV seroprevalence and DLBCL. The association observed between serologic evidence of MCV exposure and DLBCL warrants further research. Impact: MCV might be involved in the pathway of DLBCL and other lymphomas. Cancer Epidemiol Biomarkers Prev; 21(9); 1592-8. ©2012 AACR.Cancer Epidemiology Biomarkers & Prevention 07/2012; 21(9):1592-8. DOI:10.1158/1055-9965.EPI-11-1140 · 4.32 Impact Factor
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ABSTRACT: Introduction: The eukaryotic translation initiation factor 4E (eIF4E) is a key regulator of protein synthesis, and an oncogene. Its expression and activity are frequently elevated in cancer, and have been shown to correlate with poor prognosis. Efforts to target eIF4E have thus yielded much interest, with some clinical success. Areas covered: We provide an overview of eIF4E function and regulation, and its role in hematological malignancies and solid tumors. Activation of eIF4E via upstream signaling pathways that are frequently deregulated in cancer and the role of eIF4E phosphorylation are discussed. We present an updated review of different approaches to target eIF4E function in the lab and in the clinic. Expert opinion: The prospect of effectively targeting eIF4E in cancer is very attractive, because eIF4E is a common downstream node on which multiple oncogenic signaling pathways converge. However, efforts to do so have yielded limited clinical success so far. While active-site inhibitors of mammalian target of rapamycin show some promise, and inhibitors of eIF4E phosphorylation may emerge as clinical candidates, the only drug to date that has demonstrated antitumor activity associated with eIF4E inhibition in patients is ribavirin. Further studies will certainly aid the design of better compounds and rational combination therapies.Expert Opinion on Therapeutic Targets 07/2014; 18(9):1-14. DOI:10.1517/14728222.2014.937426 · 4.90 Impact Factor
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ABSTRACT: Protein translation initiation is controlled by eukaryotic initiation factor 4E (eIF-4E) binding protein 1 (4E-BP1). Phosphorylated 4E-BP1 dissociates from eIF-4E, allowing translation of transcripts mediating cell cycling, survival, and angiogenesis. The expression and phosphorylation of 4E-BP1, and influence on prognosis of diffuse large B cell lymphoma (DLBCL), is unknown. Because at least some patients with low-risk (International Prognostic Index score 0–2) DLBCL treated with standard anthracycline-based chemotherapy experience a short survival, we examined if 4E-BP1 expression and phosphorylation may provide additional prognostic information in 35 patients with low-risk DLBCL. We examined their initial diagnostic pathology specimens for 4E-BP1 expression and phosphorylation using immunohistochemistry, and we correlated these with clinical outcomes. While 4E-BP1 was uniformly expressed, there was wide distribution in its level of phosphorylation (biological activity). 4E-BP1 phosphorylation correlated strongly with overall survival (OS; P = 0.007) and progression-free survival (PFS; P = 0.02) and was the most significant independent variable for both OS and PFS on multivariable analysis. Our findings suggest that immunohistochemical evaluation of 4E-BP1 phosphorylation may help refine the prognostication of patients with low-risk DLBCL. Prospective studies in an independent cohort of patients are warranted.09/2013; 6(3). DOI:10.1007/s12308-013-0188-6