Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that can be therapeutically targeted by the flavonoid wogonin
Claudia Dürr,
Bola S. Hanna,
Angela Schulz,
Fabienne Lucas,
Manuela Zucknick,
Axel Benner,
Andrew Clear,
Sibylle Ohl,
Selcen Öztürk,
Thorsten Zenz,
Stephan Stilgenbauer,
Min Li-Weber,
Peter H. Krammer,
John G. Gribben,
Peter Lichter,
Martina Seiffert
Affiliations
Claudia Dürr
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Bola S. Hanna
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Angela Schulz
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Fabienne Lucas
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany;Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
Manuela Zucknick
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany;Oslo Center for Biostatistics and Epidemiology; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway
Axel Benner
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Andrew Clear
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
Sibylle Ohl
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Selcen Öztürk
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Thorsten Zenz
Molecular Therapy in Haematology and Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), and Department of Medicine V, University Hospital Heidelberg, Germany
Stephan Stilgenbauer
Internal Medicine III, University of Ulm, Germany
Min Li-Weber
Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Peter H. Krammer
Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
John G. Gribben
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK
Peter Lichter
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Martina Seiffert
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
Chronic lymphocytic leukemia is a malignancy of mature B cells that strongly depend on microenvironmental factors, and their deprivation has been identified as a promising treatment approach for this incurable disease. Cytokine array screening of 247 chronic lymphocytic leukemia serum samples revealed elevated levels of tumor necrosis factor (TNF) receptor-1 which were associated with poor clinical outcome. We detected a microenvironment-induced expression of TNF receptor-1 in chronic lymphocytic leukemia cells in vitro, and an aberrantly high expression of this receptor in the proliferation centers of patients’ lymph nodes. Stimulation of TNF receptor-1 with TNF-α enhanced nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activity and viability of chronic lymphocytic leukemia cells, which was inhibited by wogonin. The therapeutic effects of wogonin were analyzed in mice after adoptive transfer of Eμ-T-cell leukemia 1 (TCL1) leukemic cells. Wogonin treatment prevented leukemia development when given early after transplantation. The treatment of full-blown leukemia resulted in the loss of the TNF receptor-1 on chronic lymphocytic leukemia cells and their mobilization to blood. Targeting TNF receptor-1 signaling is therefore proposed for the treatment of chronic lymphocytic leukemia.
