High incidence of Kaposi sarcoma–associated herpesvirus–related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease

Oksenhendler, Éric; Boulanger, Emmanuelle; Galicier, Lionel; Du, Ming‐Qing; Dupin, Nicolas; Diss, Tim C.; Hamoudi, Rifat; Daniel, Marie‐Thérèse; Agbalika, F.; Boshoff, Chris; Clauvel, Jean‐Pierre; Isaacson, Peter G.; Meignin, Véronique

doi:10.1182/blood.v99.7.2331

Cited by 366 publications

(292 citation statements)

References 34 publications

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“…Kaposi's sarcoma is a cancer of blood vessel cells that often occurs in subepidermal tissues or the mucous membrane. Kaposi's sarcoma is one of the most common malignancies occurring among human immunodeficiency virus (HIV)-infected individuals (45,52). HHV-8 encodes the cytokine vIL-6, which not only inhibits immune function but also causes cancerous cells to grow.…”

Section: Discussionmentioning

confidence: 99%

“…Castleman's disease is a nonmalignant atypical lymphoproliferative disorder characterized by lymphadenopathy with angiofollicular hyperplasia and plasma cell infiltration. Virtually all HIV-infected individuals and nearly 50% of HIV-negative individuals with MCD are infected with HHV-8 (52,57). Furthermore, some HIV-infected individuals have coexistent Kaposi's sarcomas (18 to 20%) (52).…”

Section: Discussionmentioning

confidence: 99%

“…Virtually all HIV-infected individuals and nearly 50% of HIV-negative individuals with MCD are infected with HHV-8 (52,57). Furthermore, some HIV-infected individuals have coexistent Kaposi's sarcomas (18 to 20%) (52). Primary effusion lymphoma is a malignant effusion in the absence of a contiguous solid tumor mass that develops in the pleural, pericardial, or peritoneal cavity.…”

Section: Discussionmentioning

confidence: 99%

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Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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Human herpesvirus 8 (HHV-8) encodes several putative oncogenes, which are homologues to cellular host genes known to function in cell cycle regulation, control of apoptosis, and cytokine signaling. Viral interleukin (vIL-6) is believed to play an important role in the pathogenesis of Kaposi's sarcoma as well as primary effusion lymphoma and multicentric Castleman's disease. Therefore, vIL-6 is a promising target for novel therapies directed against HHV-8-associated diseases. By phage display screening of human synthetic antibody libraries, we have selected a specific recombinant antibody, called monoclonal anti-vIL-6 (MAV), binding to vIL-6. The epitope recognized by MAV was localized on the top of the D helix of the vIL-6 protein, which is a part of receptor binding site III. Consequently, MAV specifically inhibits vIL-6-mediated growth of the primary effusion lymphoma-derived cell line BCBL-1 and blocks STAT3 phosphorylation in the human hepatoma cell line HepG2. Since it was previously found that vIL-6 can also induce signals from within the cell, presumably within the endoplasmic reticulum, we fused the recombinant antibody MAV with the endoplasmic retention sequence KDEL (MAV-KDEL). As a result, COS-7 cells expressing MAV-KDEL and synthesizing vIL-6 ceased to secrete the cytokine. Moreover, we observed that vIL-6 that was bound to MAV-KDEL and retained in the endoplasmic reticulum did not induce STAT3 phosphorylation in HepG2 cells. We conclude that the activity of the intracellularly retained vIL-6 protein is neutralized by MAV-KDEL. Our results might represent a novel therapeutic strategy to neutralize virally encoded growth factors or oncogenes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Kovaleva

Bußmeyer

Rabe

et al. 2006

J Virol

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“…The human herpes virus 8 (HHV8), also known as KSHV for KS Herpes Virus, has been fully sequenced and identified in all forms of KS. It is also associated with two additional AIDS-related malignancies: primary effusion lymphomas and multicentric Castleman's disease (Chang et al, 1994;Dupin et al, 1999;Oksenhendler et al, 2002;Cesarman and Mesri, 2007). However, some important questions regarding the role of HHV8 in sarcomagenesis progression remain, such as how it interacts with the immune system.…”

Section: Introductionmentioning

confidence: 99%

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

et al. 2010

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Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-proteincoupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-c/Rac nexus in vGPCRmediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.

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“…Negativity for EBV has been previously reported in HHV-8-positive effusions without evidence of monoclonality 2,15,16 and in extranodal plasmablastic lymphoma in the context of MCD associated with body cavity effusions. 21 The identification of HHV-8 in polyclonal effusions that mimic PEL is notable in light of the association between HHV-8 and PEL, and suggests a putative model of PEL lymphomagenesis. By analogy with MCD and KS that begin as a polyclonal disease with subsequent evolution to a clonal entity in some cases, individual PEL lesions may arise by neoplastic transformation of intracavitary HHV-8-infected polyclonal precursors.…”

Section: Dear Sirmentioning

confidence: 97%

Kaposi's sarcoma‐associated herpesvirus/human herpesvirus 8‐associated polyclonal body cavity effusions that mimic primary effusion lymphomas

Ascoli

Calabrò

Giannakakis

et al. 2006

Intl Journal of Cancer

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Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV-8) is involved in the pathogenesis of Kaposi's sarcoma (KS) and 2 lymphoproliferative diseases, primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease (MCD). PEL is defined as a liquid-phase lymphoma harboring monoclonal rearrangements of immunoglobulin (Ig) variable genes or, more rarely, of T-cell receptor (TCR) genes. As a rule, these elements are used for PEL diagnosis together with the demonstration of HHV-8 infection of the tumor clone. We report here a group of five patients with MCD and KS (n = 2) or MCD only (n = 2) or KS only (n = 1); subjects with KS showed cutaneous and visceral involvement. All 5 patients developed recurrent and massive HHV-8-positive body cavity effusions, often in multiple sites, and died shortly after diagnosis. Cytological examination of effusion specimens disclosed the absence of lymphoma cells in all cases. In the context of MCD or MCD and KS, the effusion cell population was found to include 5–30% of atypical lymphoid cells with plasmacytic features and reminiscent of PEL. Our observations suggest that patients with MCD and/or KS (not exclusively in association with HIV infection) may develop recurrent HHV-8-positive body cavity effusions other than PEL, although with a similar poor outcome. Their common morphologic and molecular features appear to identify a nonlymphomatous entity. The identification of HHV-8 in polyclonal effusions that mimic PEL is notable in light of the association between HHV-8 and PEL, and suggests a putative model of PEL lymphomagenesis

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High incidence of Kaposi sarcoma–associated herpesvirus–related non-Hodgkin lymphoma in patients with HIV infection and multicentric Castleman disease

Cited by 366 publications

References 34 publications

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Kaposi's sarcoma‐associated herpesvirus/human herpesvirus 8‐associated polyclonal body cavity effusions that mimic primary effusion lymphomas

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