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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.

Author information

1
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
2
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK.
3
Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Oslo Center for Biostatistics and Epidemiology; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway.
5
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.
6
Internal Medicine III, University of Ulm, Germany.
7
Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
8
Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany m.seiffert@dkfz.de.

Abstract

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.

PMID:
29326123
PMCID:
PMC5865430
DOI:
10.3324/haematol.2017.177808
[Indexed for MEDLINE]
Free PMC Article

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