Ectopic expression of transcription factor BATF3 induces B-cell lymphomas in a murine B-cell transplantation model

// Christian Weiser 1 , Mina V. Petkova 2 , Benjamin Rengstl 1 , Claudia Doring 1 , Dorothee von Laer 3 , Sylvia Hartmann 1 , Ralf Kuppers 4, 5 , Martin-Leo Hansmann 1, 5, * and Sebastian Newrzela 1, * 1 Dr. Senckenberg Institute of Pathology, Goethe-University of Frankfurt, Medical School, Frankfurt am Main, Germany 2 Experimental and Clinical Research Center (ECRC), Medical Faculty of the Charite and Max Delbruck Center for Molecular Medicine, Berlin, Germany 3 Division of Virology, Department of Hygiene, Microbiology, Social Medicine Medical University IBK, Innsbruck, Austria 4 Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Medical School, Essen, Germany 5 German Cancer Consortium (DKTK), Heidelberg, Germany * Shared senior authors Correspondence to: Ralf Kuppers, email: ralf.kueppers@uk-essen.de Keywords: BATF3; B-cell immunology; B-cell lymphoma; germinal center; oncogene Received: March 13, 2017     Accepted: February 24, 2018     Published: March 23, 2018 ABSTRACT The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients. Intriguingly, BATF3-expressing B lymphocytes readily induced B-cell lymphomas after characteristic latencies, whereas T-cell transplanted animals remained healthy throughout the observation time. Further analyses revealed a germinal center B-cell-like phenotype of most BATF3-initiated lymphomas. In a multiple myeloma cell line, BATF3 inhibited BLIMP1 expression, potentially illuminating an oncogenic action of BATF3 in B-cell lymphomagenesis. In conclusion, BATF3 overexpression induces malignant transformation of mature B cells and might serve as a potential target in B-cell lymphoma treatment.