Page 144 - Haematologica-April 2018

Correspondence:
m.seiffert@dkfz.de
Received: July 31, 2017. Accepted: January 11, 2018. Pre-published: January 11, 2018.
doi:10.3324/haematol.2017.177808
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/4/688
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Chronic Lymphocytic Leukemia
Tumor necrosis factor receptor signaling is a driver of chronic lymphocytic leukemia that
can be therapeutically targeted by the flavonoid wogonin
Claudia Dürr,1 Bola S. Hanna,1 Angela Schulz,1 Fabienne Lucas,1,2
Manuela Zucknick,3,4 Axel Benner,3 Andrew Clear,2 Sibylle Ohl,1 Selcen Öztürk,1 Thorsten Zenz,5 Stephan Stilgenbauer,6 Min Li-Weber,7 Peter H. Krammer,7 John G. Gribben,2 Peter Lichter1 and Martina Seiffert1
1Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, UK; 3Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany; 4Oslo Center for Biostatistics and Epidemiology; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway; 5Molecular 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; 6Internal Medicine III, University of Ulm, Germany and 7Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
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 Em-T-cell leukemia 1 (TCL1) leukemic cells. Wogonin treatment prevented leukemia develop- ment 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.
Introduction
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy that is tightly regu- lated by and dependent on microenvironmental stimuli provided in lymphoid tis- sues.1 CLL cells in this protective niche show increased resistance to spontaneous and drug-induced apoptosis which is causative for CLL progression and relapse. In vitro studies using co-cultures of CLL and non-malignant accessory cells mirrored this dependency, and identified several CLL-relevant factors and pathways.2-4 Comparative gene expression profiling of CLL cells isolated from peripheral blood (PB), bone marrow (BM) and lymph nodes (LN) further identified enhanced B-cell receptor (BCR)-mediated signaling and nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activity in the lymphoid microenvironment compared to blood.5 In accordance with this, CLL cell migratory capability and tissue homing were shown to influence disease pathogenesis and progression.6 Data from clinical trials revealed that treatment with kinase inhibitors targeting BTK, SYK or PI3K-d leads to transient lymphocytosis accompanied by LN shrinkage due to CLL cell mobilization to PB.7-9 This impairment of CLL cell homing to lymphoid tissues sub-
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