AIDS-related primary effusion lymphoma (PEL) is an HIV-associated malignancy characterized by the ability of the tumor cells to specifically home in the serous body cavities. Here we used gene ...expression profile analysis (about 12 000 genes) to further define the phenotype of PEL and to investigate the lymphoma relationship to normal B cells and to other tumor subtypes, including non-Hodgkin lymphomas (NHLs) of immunocompetent hosts and AIDS-associated NHL (AIDS-NHL). The results showed that PEL displayed a common gene expression profile that is clearly distinct from all NHLs of immunocompetent hosts and AIDS-NHL subtypes and, in contrast to those, is not related to germinal center (GC) or memory B cells. The gene expression profile of PEL was defined as plasmablastic because it showed features of both immunoblasts identified by Epstein-Barr virus (EBV)–transformed lymphoblastoid cell lines and AIDS immunoblastic lymphoma, and plasma cells, as defined by multiple myeloma cell lines. Finally, our results identify a set of genes specifically expressed in PEL tumor cells. Their expression was validated at the protein level, suggesting their potential pathogenetic and clinical significance.
Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus (EBV) associated lymphoid proliferations occurring in the setting of ...immunosuppression associated with solid organ transplantation. Some PT-LPDs regress after a reduction in immunosuppression, whereas others progress despite aggressive therapy. Previously defined histopathologic categories do not correlate with clonality, and neither histopathology nor clonality has reliably predicted their clinical behavior. Recently, correlative clinical, morphological, and molecular genetic analysis has suggested that PT-LPDs are divisible into three distinct clinically relevant categories as follows: (1) plasmacytic hyperplasia: most commonly arise in the oropharynx or lymph nodes, are nearly always polyclonal, usually contain multiple EBV infectious events or only a minor cell population infected by a single form of EBV, and lack oncogene or tumor suppressor gene alterations; (2) polymorphic lymphoproliferative disorders: may arise in lymph nodes or extranodal sites including the gastrointestinal tract and lungs, are nearly always monoclonal based on the presence of clonal immunoglobulin gene rearrangements, usually contain a single form of EBV, and lack oncogene or tumor suppressor gene alterations; and (3) malignant lymphoma or multiple myeloma: present with widely disseminated disease frequently including the bone marrow, are monoclonal based on clonal immunoglobulin gene rearrangements, contain a single form of EBV, and contain alterations of one or more oncogenes or tumor suppressor genes (c-myc, ras, p53). Thus, proto-oncogene and tumor suppressor gene alterations appear to be associated with disease progression and an often fatal clinical outcome. Furthermore, multiple PT-LPD lesions occurring in the same individual but in multiple anatomic sites, either simultaneously or dysynchronously over time, may show distinct clonal immunoglobulin gene rearrangement patterns and evidence of infection by different forms of EBV, suggesting that each lesion represents a distinct clonal neoplasm that may show distinctive clinical behavior. Therefore, whenever possible, a biopsy of each one of the several PT-LPD lesions occurring in an individual should be obtained to derive a true assessment of the pathobiological nature and clinical aggressiveness of an individual's disease.
Primary effusion lymphoma (PEL) is a very rare subgroup of B-cell lymphomas presenting as pleural, peritoneal and pericardial neoplastic effusions in the absence of a solid tumor mass or recognizable ...nodal involvement. There is strong evidence that Kaposi's sarcoma-associated herpesvirus (KSHV) is a causal agent of PEL. PEL tumor cells are latently infected by KSHV with consistent expression of several viral proteins and microRNAs that can affect cellular proliferation, differentiation and survival. The most relevant data on pathogenesis and biology of KSHV have been provided by studies on PEL-derived cell lines. Fourteen continuous cell lines have been established from the malignant effusions of patients with AIDS-associated and non-AIDS-associated PEL. These KSHV+ EBV+/- cell lines are well characterized, authenticated and mostly available from public biological resource centers. The PEL cell lines display unique features and are clearly distinct from other lymphoma cell lines. PEL cell lines represent an indispensable tool for the understanding of KSHV biology and its impact on the clinical manifestation of PEL. Studies on PEL cell lines have shown that a number of viral genes, expressed during latency or lytic life cycle, have effects on cell binding, proliferation, angiogenesis and inflammation. Also, PEL cell lines are important model systems for the study of the disorder of PEL including the lack of invasive or destructive growth patterns and the peculiar propensity of PEL to involve body cavity surfaces.
Primary effusion lymphomas (PELs) characterized by infection with the Kaposi's sarcoma herpesvirus (KSHV; also called human herpesvirus 8) depend on the expression of the viral FADD‐like ...interleukin‐1‐β‐converting enzyme (FLICE)/caspase‐8‐inhibitory protein (vFLIP) for their survival. This effect is achieved by activation of the transcription factor nuclear factor‐κB (NF‐κB). Tumour necrosis factor (TNF) receptor‐associated factors (TRAFs) are direct mediators of NF‐κB signalling by TNF family receptors and the Epstein–Barr virus oncoprotein latent membrane protein 1 and so we assessed the role of TRAFs in signalling by vFLIP. Here, we report the identification of a TRAF‐interacting motif (PYQLT) in vFLIP, which is not present in other FLIP molecules. We show that vFLIP directly binds to TRAF2 in vitro and in PEL cells. TRAF2 and TRAF3 are required for induction of NF‐κB and associated cell survival, as well as Jun amino‐terminal kinase phosphorylation by vFLIP, whereas TRAF1, TRAF5 and TRAF6 are dispensable. Mutations in the P93 or Q95 amino acids within the TRAF‐interacting motif of vFLIP abolish its ability to bind to TRAF2 and to signal to NF‐κB. TRAF2, but not TRAF3, mediates the association of vFLIP with the IκB kinase complex. These data indicate that vFLIP uses TRAF2 and TRAF3 for signalling to NF‐κB, which is crucial for KSHV‐associated lymphomagenesis.
To evaluate the safety and efficacy of a sequential chemotherapy plus radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma.
Thirty-five patients received an ...abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab.
After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT.
Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients.
Strong immunohistochemical reactivity for p53 tumor suppressor gene product has been reported in a variety of different human malignancies including CD30- (Ki-1) positive anaplastic large cell ...lymphoma (ALCL). Although high levels of p53 protein have been interpreted as abnormal, rapidly proliferating benign and neoplastic lymphoid cells may have increased p53 expression in the absence of structural alterations. On the other hand, mutations in the p53 gene can lead to a lack of p53 protein production. Structural alterations of the p53 gene have not been documented in cases of ALCL and the mechanism for an abnormal pattern of p53 expression in these lymphomas has not been elucidated. Therefore, to determine whether an altered pattern of p53 expression correlates with mutations in the p53 locus in ALCL, we analyzed the expression of p53 protein immunohistochemically, compared it with the proliferation index using monoclonal antibody Ki-67, and assessed the presence of mutations in exons 5 though 9 of the p53 gene using a single-strand conformation polymorphism assay in a panel of 17 ALCLs. Furthermore, we studied the presence of allelic deletions of chromosome 17p by restriction fragment length polymorphism analysis. We found significant levels of p53 protein expression in 12 of the 15 cases studied, but identified mutations in only one of 17 cases. An allelic deletion in chromosome 17p was identified only in the one case containing a mutated p53 gene. Whereas the case containing structural alterations in the p53 gene did have strong p53 immunoreactivity, 11 cases that lacked p53 mutations in the regions examined also had significant levels of p53. Thus, our studies indicate that strong immunohistochemical reactivity for p53 is not a reliable indicator of the presence of structural alterations of p53 gene exons 5 through 9 in ALCL.
Kaposi's sarcoma-associated virus (KSHV) is the causative agent of Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL). The KSHV G protein-couple receptor (vGPCR) is a homologue of the human ...IL-8 receptor that signals constitutively, activates mitogen- and stress-activated kinases, and induces transcription via multiple transcription factors including AP-1 and NFkappaB. Furthermore, vGPCR causes cellular transformation in vitro and leads to KS-like tumors in transgenic mouse models. vGPCR has therefore become an exciting potential therapeutic target for KSHV-mediated disease, but its signaling properties need to be better understood in the context of KSHV-infected hematopoietic cells. We recently described a PEL cell line that expresses vGPCR via an inducible promoter and have shown that vGPCR has broad capabilities of affecting cellular and viral transcription patterns in this highly relevant cell type. To elucidate the predominant signaling pathways used by vGPCR in PEL cells, we have used reporter gene assays to measure vGPCR activity in the presence of various pharmacologic enzyme inhibitors and plasmid constructs. We show that vGPCR-induced activation of AP-1 and CREB is mediated cooperatively by a Gq-ERK-1/2 and a Gi-PI3K-Src axis. Furthermore, unlike in other cell types, NFkappaB activation by vGPCR seems not to be substantially mediated by Gi or PI3K/Akt in PEL cells.
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