title: Mature T-cell lymphomagenesis induced by retroviral insertional activation of Janus kinase 1.
abstract: Retroviral vectors (RVs) are powerful tools in clinical gene therapy. However, stable genomic integration of RVs can be oncogenic, as reported in several animal models and in clinical trials. Previously, we observed that T-cell receptor (TCR) polyclonal mature T cells are resistant to transformation after gammaretroviral transfer of (proto-)oncogenes, whereas TCR-oligoclonal T cells were transformable in the same setting. Here, we describe the induction of a mature T-cell lymphoma (MTCL) in TCR-oligoclonal OT-I transgenic T cells, transduced with an enhanced green fluorescent protein (EGFP)-encoding gammaretroviral vector. The tumor cells were of a mature T-cell phenotype and serially transplantable. Integration site analysis revealed a proviral hit in Janus kinase 1 (Jak1), which resulted in Jak1 overexpression and Jak/STAT-pathway activation, particularly via signal transducer and activator of transcription 3 (STAT3). Specific inhibition of Jak1 markedly delayed tumor growth. A systematic meta-analysis of available gene expression data on human mature T-cell lymphomas/leukemias confirmed the relevance of Jak/STAT overexpression in sporadic human T-cell tumorigenesis. To our knowledge, this is the first study to describe RV-associated insertional mutagenesis in mature T cells.
authors.affiliation: Senckenberg Institute of Pathology, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Heinrich
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rengstl
authors.forename: Alexander
authors.initials: A
authors.lastname: Muik
authors.forename: Mina
authors.initials: M
authors.lastname: Petkova
authors.forename: Frederike
authors.initials: F
authors.lastname: Schmid
authors.forename: Robin
authors.initials: R
authors.lastname: Wistinghausen
authors.forename: Kathrin
authors.initials: K
authors.lastname: Warner
authors.forename: Giuliano
authors.initials: G
authors.lastname: Crispatzu
authors.forename: Martin-Leo
authors.initials: ML
authors.lastname: Hansmann
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Newrzela
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005091:Exons; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016254:Mutagenesis, Insertional / Q000379:methods*; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D049452:Green Fluorescent Proteins; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1