David Sanchez-Martin1, Thomas S Uldrick2, Hyeongil Kwak1, Hidetaka Ohnuki1, Mark N Polizzotto2, Christina M Annunziata3, Mark Raffeld4, Kathleen M Wyvill2, Karen Aleman2, Victoria Wang2, Vickie A Marshall5,6, Denise Whitby5,6, Robert Yarchoan2, Giovanna Tosato1. 1. Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD, USA. 2. HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland, USA. 3. Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. 4. Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA. 5. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 6. Viral Oncology Section, AIDS and Cancer Virus Program, Leidos Biomedical, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Abstract
Background: Primary effusion lymphoma (PEL) is a Kaposi's sarcoma herpes virus (KSHV)-induced lymphoma that typically arises in body cavities of HIV-infected patients. PEL cells are often co-infected with Epstein-Barr virus (EBV). "PEL-like" lymphoma is a KSHV-unrelated lymphoma that arises in body cavities of HIV-negative patients. "PEL-like" lymphoma is sometimes EBV positive. The derivation of PEL/"PEL-like" cells is unclear. Methods: Mesothelial cells were cultured from body cavity effusions of 23 patients. Cell proliferation, cytokine secretion, marker phenotypes, KSHV/EBV infection, and clonality were evaluated by standard methods. Gene expression was measured by quantitative polymerase chain reaction and immunoblotting. A mouse model of PEL (3 mice/group) was used to evaluate tumorigenicity. Results: We found that the mesothelia derived from six effusions of HIV-infected patients with PEL or other KSHV-associated diseases contained rare KSHV + or EBV + mesothelial cells. After extended culture (16-17 weeks), some mesothelial cells underwent a trans-differentiation process, generating lymphoid-type CD45 + /B220 + , CD5 + , CD27 + , CD43 + , CD11c + , and CD3 - cells resembling "B1-cells," most commonly found in mouse body cavities. These "B1-like" cells were short lived. However, long-term KSHV + EBV - and EBV + KSHV - clonal cell lines emerged from mesothelial cultures from two patients that were clonally distinct from the monoclonal or polyclonal B-cell populations found in the patients' original effusions. Conclusions: Mesothelial-to-lymphoid transformation is a newly identified in vitro process that generates "B1-like" cells and is associated with the emergence of long-lived KSHV or EBV-infected cell lines in KSHV-infected patients. These results identify mesothelial cultures as a source of PEL cells and lymphoid cells in humans. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.
Background: Primary effusion lymphoma (PEL) is a Kaposi's sarcoma herpes virus (KSHV)-induced lymphoma that typically arises in body cavities of HIV-infectedpatients. PEL cells are often co-infected with Epstein-Barr virus (EBV). "PEL-like" lymphoma is a KSHV-unrelated lymphoma that arises in body cavities of HIV-negative patients. "PEL-like" lymphoma is sometimes EBV positive. The derivation of PEL/"PEL-like" cells is unclear. Methods: Mesothelial cells were cultured from body cavity effusions of 23 patients. Cell proliferation, cytokine secretion, marker phenotypes, KSHV/EBV infection, and clonality were evaluated by standard methods. Gene expression was measured by quantitative polymerase chain reaction and immunoblotting. A mouse model of PEL (3 mice/group) was used to evaluate tumorigenicity. Results: We found that the mesothelia derived from six effusions of HIV-infectedpatients with PEL or other KSHV-associated diseases contained rare KSHV + or EBV + mesothelial cells. After extended culture (16-17 weeks), some mesothelial cells underwent a trans-differentiation process, generating lymphoid-type CD45 + /B220 + , CD5 + , CD27 + , CD43 + , CD11c + , and CD3 - cells resembling "B1-cells," most commonly found in mouse body cavities. These "B1-like" cells were short lived. However, long-term KSHV + EBV - and EBV + KSHV - clonal cell lines emerged from mesothelial cultures from two patients that were clonally distinct from the monoclonal or polyclonal B-cell populations found in the patients' original effusions. Conclusions: Mesothelial-to-lymphoid transformation is a newly identified in vitro process that generates "B1-like" cells and is associated with the emergence of long-lived KSHV or EBV-infected cell lines in KSHV-infectedpatients. These results identify mesothelial cultures as a source of PEL cells and lymphoid cells in humans. Published by Oxford University Press 2017. This work is written by US Government employees and is in the public domain in the US.
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