Characterization of c-Kit expression and activation in KSHV-infected endothelial cells

Douglas, Janet L.; Whitford, Jill G.; Moses, Ashlee V.

doi:10.1016/j.virol.2009.05.011

Cited by 7 publications

(5 citation statements)

References 32 publications

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“…Previous work demonstrated CD117 expression in vitro on latently infected dermal ECs (43,54) and on cells present in large numbers in KS lesions, with 93% of CD117 + lesions LANA + (55). Clinical trials testing the efficacy of Gleevec/imatinib mesylate in the treatment of KS showed promise, with demonstrated clinical and histological regression of cutaneous KS lesions (56).…”

Section: Resultsmentioning

confidence: 95%

Mast Cell Activation and KSHV Infection in Kaposi Sarcoma

Ayers

Barbachano-Guerrero

McAllister

et al. 2018

Clinical Cancer Research

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Kaposi sarcoma (KS) is a vascular tumor initiated by infection of endothelial cells (ECs) with KS-associated herpesvirus (KSHV). KS is dependent on sustained proinflammatory signals provided by intralesional leukocytes and continued infection of new ECs. However, the sources of these cytokines and infectious virus within lesions are not fully understood. Here, mast cells (MCs) are identified as proinflammatory cells within KS lesions that are permissive for, and activated by, infection with KSHV. Three validated MC lines were used to assess permissivity of MCs to infection with KSHV and to evaluate MCs activation following infection. Biopsies from 31 AIDS-KS cases and 11 AIDS controls were evaluated by IHC for the presence of MCs in KS lesions and assessment of MC activation state and infection with KSHV. Plasma samples from 26 AIDS-KS, 13 classic KS, and 13 healthy adults were evaluated for levels of MC granule contents tryptase and histamine. In culture, MCs supported latent and lytic KSHV infection, and infection-induced MC degranulation. Within KS lesions, MCs were closely associated with spindle cells. Furthermore, MC activation was extensive within patients with KS, reflected by elevated circulating levels of tryptase and a histamine metabolite. One patient with clinical signs of extensive MC activation was treated with antagonists of MC proinflammatory mediators, which resulted in a rapid and durable regression of AIDS-KS lesions. Using complimentary and studies we identify MCs as a potential long-lived reservoir for KSHV and a source of proinflammatory mediators within the KS lesional microenvironment. In addition, we identify MC antagonists as a promising novel therapeutic approach for KS. .

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Section: Resultsmentioning

confidence: 95%

Mast Cell Activation and KSHV Infection in Kaposi Sarcoma

Ayers

Barbachano-Guerrero

McAllister

et al. 2018

Clinical Cancer Research

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“…NCT00090987) and achieved a partial regression of cutaneous KS lesions in some patients (57,58). Inhibition of c-kit and/or platelet-derived growth factor (PDGF) receptors by imatinib may have contributed to this observation (59,60). However, imatinib does not inhibit the tyrosine kinase function of KSHV ORF21/TK ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use

Beauclair

Naimo

Dubich

et al. 2020

J Virol

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is the cause of three human malignancies: Kaposi’s sarcoma, primary effusion lymphoma, and the plasma cell variant of multicentric Castleman disease. Previous research has shown that several cellular tyrosine kinases play crucial roles during several steps in the virus replication cycle. Two KSHV proteins also have protein kinase function: open reading frame (ORF) 36 encodes a serine-threonine kinase, while ORF21 encodes a thymidine kinase (TK), which has recently been found to be an efficient tyrosine kinase. In this study, we explore the role of the ORF21 tyrosine kinase function in KSHV lytic replication. By generating a recombinant KSHV mutant with an enzymatically inactive ORF21 protein, we show that the tyrosine kinase function of ORF21/TK is not required for the progression of the lytic replication in tissue culture but that it is essential for the phosphorylation and activation to toxic moieties of the antiviral drugs zidovudine and brivudine. In addition, we identify several tyrosine kinase inhibitors, already in clinical use against human malignancies, which potently inhibit not only ORF21 TK kinase function but also viral lytic reactivation and the development of KSHV-infected endothelial tumors in mice. Since they target both cellular tyrosine kinases and a viral kinase, some of these compounds might find a use in the treatment of KSHV-associated malignancies. IMPORTANCE Our findings address the role of KSHV ORF21 as a tyrosine kinase during lytic replication and the activation of prodrugs in KSHV-infected cells. We also show the potential of selected clinically approved tyrosine kinase inhibitors to inhibit KSHV TK, KSHV lytic replication, infectious virion release, and the development of an endothelial tumor. Since they target both cellular tyrosine kinases supporting productive viral replication and a viral kinase, these drugs, which are already approved for clinical use, may be suitable for repurposing for the treatment of KSHV-related tumors in AIDS patients or transplant recipients.

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“…102,124,[133][134][135][136] These experiments support the classification of KSHV as a bona fide human tumor virus; however, tissue culture systems, by design, are finely tuned to respond to pro-growth signals with drastic changes in cell pheno-…”

mentioning

confidence: 68%

“…The KSHV miRNAs in isolation also induce trans‐differentiation and hallmarks of transformation 76,78,97,98,131,132 . In culture, KSHV can transform both endothelial and mesenchymal lineage precursors, as well as experimental cell models, to the point that they form tumors as xenografts in immune‐deficient mice 102,124,133–136 . These experiments support the classification of KSHV as a bona fide human tumor virus; however, tissue culture systems, by design, are finely tuned to respond to pro‐growth signals with drastic changes in cell phenotypes.…”

Section: The Lineage Of the Ks Tumor Cellmentioning

confidence: 81%

Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it?

Damania

Dittmer

2023

Journal of Medical Virology

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This review will provide an overview of the notion that Kaposi sarcoma (KS) is a disease that manifests under diverse and divergent circumstances. We begin with a historical introduction of KS and KS-associated herpesvirus (KSHV), highlight the diversity of clinical presentations of KS, summarize what we know about the cell of origin for this tumor, explore KSHV viral load as a potential biomarker for acute KSHV infections and KS-associated complications, and discuss immune modulators that impact KSHV infection, KSHV persistence, and KS disease.

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Characterization of c-Kit expression and activation in KSHV-infected endothelial cells

Cited by 7 publications

References 32 publications

Mast Cell Activation and KSHV Infection in Kaposi Sarcoma

Mast Cell Activation and KSHV Infection in Kaposi Sarcoma

Targeting Kaposi's Sarcoma-Associated Herpesvirus ORF21 Tyrosine Kinase and Viral Lytic Reactivation by Tyrosine Kinase Inhibitors Approved for Clinical Use

Today's Kaposi sarcoma is not the same as it was 40 years ago, or is it?

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