title: B lymphocytes from patients with a hypomorphic mutation in STAT3 resist Epstein-Barr virus-driven cell proliferation.
abstract: Epstein-Barr virus (EBV) oncogenes exert potent B cell proliferative effects. EBV infection gives rise to B cell lines that readily proliferate in culture. This ability of EBV represents a powerful tool to study cell proliferation. In efforts to delineate the contribution of signal transducer and activator of transcription 3 (STAT3) toward EBV-driven cell proliferation, we have discovered that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES) resist such EBV oncogene-driven outgrowth of cells. Patients with AD-HIES have a dominant negative mutation in their STAT3 gene which renders most of the protein nonfunctional. Exposure of healthy subject-derived B cells to EBV resulted in early activation of STAT3, rapidly followed by increased expression of its mRNA and protein. STAT3 upregulation preceded the expression of EBNA2, temporally one of the first viral oncogenes to be expressed. We found that STAT3 was necessary for subsequent survival and for proliferation of EBV-infected cells past the S phase of the cell cycle. Consequently, B cells from AD-HIES patients were prone to dying and accumulated in the S phase, thereby accounting for impaired cell outgrowth. Of importance, we have now identified a cohort of patients with a primary immunodeficiency disorder whose B cells oppose EBV-driven proliferative signals. These findings simultaneously reveal how EBV manipulates host STAT3 even before expression of viral oncogenes to facilitate cell survival and proliferation, processes fundamental to EBV lymphomagenesis.
authors.affiliation: Pediatric Infectious Diseases, Department of Pediatrics, and Stony Brook Children's Hospital, Stony Brook University School of Medicine, Stony Brook, New York, USA.
authors.forename: Siva
authors.initials: S
authors.lastname: Koganti
authors.forename: Amanda
authors.initials: A
authors.lastname: de la Paz
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Sumita
authors.initials: S
authors.lastname: Bhaduri-McIntosh
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000166:cytology / Q000821:virology*; D001483:Base Sequence; D049109:Cell Proliferation; D002648:Child; D017931:DNA Primers; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D016196:S Phase; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human