HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells.
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SUBMITTER: Gonnella R
PROVIDER: S-EPMC9959463 | biostudies-literature | 2023 Feb
REPOSITORIES: biostudies-literature
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HSPs/STAT3 Interplay Sustains DDR and Promotes Cytokine Release by Primary Effusion Lymphoma Cells.
Gonnella Roberta R Arena Andrea A Zarrella Roberta R Gilardini Montani Maria Saveria MS Santarelli Roberta R Cirone Mara M
International journal of molecular sciences 20230215 4
Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma, against which current therapies usually fail. In the present study, we show that targeting HSPs, such as HSP27, HSP70 and HSP90, could be an efficient strategy to reduce PEL cell survival, as it induces strong DNA damage, which correlated with an impairment of DDR. Moreover, as HSP27, HSP70 and HSP90 cross talk with STAT3, their inhibition results in STAT3 de-phosphorylation and. On the other hand, the inhibition of STAT3 ...[more]
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Project description:Primary effusion lymphoma (PEL) is a rare, aggressive B-cell lymphoma that usually localizes to serous body cavities to subsequently form effusions in the absence of a discrete mass. Although some tumors can develop in extracavitary locations, the areas most often affected include the peritoneum, pleural space, and the pericardium. PEL is associated with the presence of human herpesvirus 8 (HHV8), also called the Kaposi sarcoma-associated herpesvirus (KSHV), with some variability in transformation potential suggested by frequent coinfection with the Epstein-Barr virus (EBV) (~80%), although the nature of the oncogenesis is unclear. Most patients suffering with this disease are to some degree immunocompromised (e.g., Human immunodeficiency virus (HIV) infection or post-solid organ transplantation) and, even with aggressive treatment, prognosis remains poor. There is no definitive guideline for the treatment of PEL, although CHOP-like regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone) are frequently prescribed and, given the rarity of this disease, therapeutic focus is being redirected to personalized and targeted approaches in the experimental realm. Current clinical trials include the combination of lenalidomide and rituximab into the EPOCH regimen and the treatment of individuals with relapsed/refractory EBV-associated disease with tabelecleucel.
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Project description: Not available
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Project description:Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lytic cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated γH2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.
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Project description:BackgroundPrimary effusion lymphoma (PEL) is a non-Hodgkin lymphoma that is exclusively generated by body cavity effusion. Primary effusion lymphoma develops in patients infected with human immunodeficiency virus (HIV) and is associated with the human herpes virus (HHV)-8 infection. However, there are sporadic cases without HHV-8 infections or any history of immunodeficiency, called 'PEL-like lymphoma'.Case summaryAn 83-year-old man was admitted to our institution because of shortness of breath, fatigue, and facial oedema. Laboratory findings were unremarkable, including negative results for HIV antibodies. Transthoracic echocardiography revealed massive pericardial effusion surrounding the entire heart, which resulted in the early diastolic collapse of the right ventricular free wall, indicating elevated intra-pericardial pressure. He underwent pericardial centesis and 700 mL of pericardial fluid was drained. Adenosine deaminase (ADA) in the pericardial effusion showed an abnormally high value of 221 U/L. Cytological examination revealed a cellular population compatible with diffuse large B-cell lymphoma with prominent blastic characteristics and negative for HHV-8 latent nuclear antigens. Thus, the patient was diagnosed with HHV-8 unrelated HIV-negative PEL-like lymphoma. He was followed for more than 10 months in complete remission after a single pericardial drainage without any chemotherapy.DiscussionExhaustive drainage of the lymphomatous effusion may induce complete remission in some patients with PEL-like lymphoma. Furthermore, the ADA value in the pericardial effusion may serve as a valuable guide to facilitate the accurate diagnosis of PEL-like lymphoma.
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