Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies

Ramos, Juan Carlos; Sin, Sang-Hoon; Staudt, Michelle R.; Roy, Debasmita; Vahrson, Wolfgang; Dezube, Bruce J.; Harrington, William; Dittmer, Dirk P.

doi:10.1002/ijc.26302

Cited by 15 publications

(11 citation statements)

References 25 publications

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“…Interestingly, the transcriptomic profile of EBV-positive benign lymphadenophathy was described as closer to BL than to post-transplant lymphoproliferative disease [32], supporting EBV-positive lymphadenopathy as a critical step leading to lymphomagenesis, similar to what we suggest here for C . burnetii infection [32].…”

Section: Discussionsupporting

confidence: 78%

A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever

et al. 2019

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Coxiella burnetii , the agent causing Q fever, has been associated with B-cell non-Hodgkin lymphoma (NHL). To better clarify this link, we analysed the genetic transcriptomic profile of peripheral blood leukocytes from patients with C . burnetii infection to identify possible links to lymphoma. Microarray analyses revealed that 1189 genes were expressed differently (p <.001 and fold change ≥4) in whole blood of patients with C . burnetii infection compared to controls. In addition, 95 genes expressed in patients with non-Hodgkin lymphoma (NHL) and in patients with C . burnetii persistent infection have allowed us to establish the ‘ C . burnetii -associated NHL signature’. Among these, 33 genes previously found modulated in C . burnetii -associated -NHL by the microarray analysis were selected and their mRNA expression levels were measured in distinct C . burnetii -induced pathologies, namely, acute Q fever, focalized persistent infection, lymphadenitis and C . burnetii -associated NHL. Specific genes involved in anti-apoptotic process were found highly expressed in leukocytes from patients with C . burnetii associated-NHL: MIR17HG , REL and SP100 . This signature differed from that found for NHL-control group. Patients with C . burnetii lymphadenitis presented significant elevated levels of BCL2 and ETS1 mRNAs. Altogether, we identified a specific transcriptionnal signature for NHL during C . burnetii infection reflecting the up-regulation of anti-apoptotic processes and the fact that lymphadenitis might constitute a critical step towards lymphomagenesis.

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Section: Discussionsupporting

confidence: 78%

A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever

et al. 2019

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“…In fact, the KS tumor microenvironment is dysregulated and associated with abundant proangiogenic and proinflammatory cytokines (14). High levels of IL-6, TNF-α and IL-10 are present in sera of KS patients whereas IL-1β transcripts are upregulated in KS biopsies (15). …”

Section: Introductionmentioning

confidence: 99%

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

et al. 2017

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Toll-like receptors (TLR) are conserved immune sensors mediating antimicrobial and antitumoral responses, but recent evidence implicates them in promoting carcinogenesis in certain cancers. Kaposi’s sarcoma (KS) is caused by infection of Kaposi’s sarcoma-associated herpesvirus (KSHV) and is characterized by uncontrolled neoangiogenesis and inflammation. Here we show that TLR4 is upregulated in KSHV-infected spindle tumor cells in human KS lesions. In a model of KSHV-induced cellular transformation, KSHV upregulated expression of TLR4, its adaptor MyD88, and coreceptors CD14 and MD2. KSHV induction of TLR4 was mediated by multiple viral microRNAs. Importantly, the TLR4 pathway was activated constitutively in KSHV-transformed cells resulting in chronic induction of IL-6, IL-1β and IL-18. Accordingly, IL-6 mediated constitutive activation of the STAT3 pathway, an essential event for uncontrolled cellular proliferation and transformation. TLR4 stimulation with lipopolysaccharides or live bacteria enhanced tumorigenesis while TLR4 antagonist CLI095 inhibited it. These results highlight an essential role of the TLR4 pathway and chronic inflammation in KSHV-induced tumorigenesis, which helps explain why HIV-infected patients, who frequently suffer from opportunistic bacterial infections and metabolic complications, frequently develop KS.

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“…As compared to other herpesvirus polymerase inhibitors, which are purine analogs, AZT is a thymidine analog and appears to be a superior substrate for EBV and KSHV thymidine kinases [11]. Furthermore, we have previously demonstrated that AZT, but not GCV, inhibited nuclear factor κB (NF- κB) activity, thus inducing EBV lytic gene expression and apoptosis in primary type I latency EBV+ BL cell lines [12,13]. The drug methotrexate (MTX) inhibits thymidylate synthase, thus blocking de novo synthesis of dTMP and increasing the likelihood of AZT incorporation into DNA [14].…”

Section: Rationale For the Use Of Zidovudine In Ebv+ Lymphomasmentioning

confidence: 99%

Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

Bayraktar

Diaz

Ashlock

et al. 2013

Leukemia & Lymphoma

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Treatment of Epstein–Barr virus (EBV)-related lymphomas with lytic-inducing agents is an attractive targeted approach for eliminating virus-infected tumor cells. Zidovudine (AZT) is an excellent substrate for EBV-thymidine kinase: it can induce EBV lytic gene expression and apoptosis in primary EBV+ lymphoma cell lines. We hypothesized that the combination of AZT with lytic-inducing chemotherapy agents would be effective in treating EBV+ lymphomas. We report a retrospective analysis of 19 patients with aggressive EBV+ non-Hodgkin lymphoma, including nine cases of acquired immune deficiency syndrome-associated primary central nervous system lymphoma (AIDSPCNSL) treated with AZT-based chemotherapy. Our results demonstrate that high-dose AZT–methotrexate is efficacious in treating highly aggressive systemic EBV+ lymphomas in the upfront setting. In primary EBV+ lymphoma cell lines, the combination of AZT with hydroxyurea resulted in synergistic EBV lytic induction and cell death. Further, AZT–hydroxyurea treatment resulted in dramatic responses in patients with AIDSPCNSL. The combination of AZT with chemotherapy, especially lytic-inducing agents, should be explored further in clinical trials for the treatment of EBV-related lymphomas.

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Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies

Cited by 15 publications

References 25 publications

A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever

A transcriptional signature associated with non-Hodgkin lymphoma in the blood of patients with Q fever

TLR4-Mediated Inflammation Promotes KSHV-Induced Cellular Transformation and Tumorigenesis by Activating the STAT3 Pathway

Zidovudine-based lytic-inducing chemotherapy for Epstein–Barr virus-related lymphomas

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