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Haematologica. 2018 Apr;103(4):688-697. doi: 10.3324/haematol.2017.177808. Epub 2018 Jan 11.

Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that can be therapeutically targeted by the flavonoid wogonin.

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Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK.
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.
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.
Internal Medicine III, University of Ulm, Germany.
Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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 -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.

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