title: HSP90 promotes Burkitt lymphoma cell survival by maintaining tonic B-cell receptor signaling.
abstract: Burkitt lymphoma (BL) is an aggressive B-cell neoplasm that is currently treated by intensive chemotherapy in combination with anti-CD20 antibodies. Because of their toxicity, current treatment regimens are often not suitable for elderly patients or for patients in developing countries where BL is endemic. Targeted therapies for BL are therefore needed. In this study, we performed a compound screen in 17 BL cell lines to identify small molecule inhibitors affecting cell survival. We found that inhibitors of heat shock protein 90 (HSP90) induced apoptosis in BL cells in vitro at concentrations that did not affect normal B cells. By global proteomic and phosphoproteomic profiling, we show that, in BL, HSP90 inhibition compromises the activity of the pivotal B-cell antigen receptor (BCR)-proximal effector spleen tyrosine kinase (SYK), which we identified as an HSP90 client protein. Consistently, expression of constitutively active TEL-SYK counteracted the apoptotic effect of HSP90 inhibition. Together, our results demonstrate that HSP90 inhibition impairs BL cell survival by interfering with tonic BCR signaling, thus providing a molecular rationale for the use of HSP90 inhibitors in the treatment of BL.
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Walter
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Pan
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Doebele
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Stem Cell Institute, Cambridge, United Kingdom.
authors.forename: Federico
authors.identifier: 0000-0002-8970-6610
authors.initials: F
authors.lastname: Comoglio
authors.affiliation: Molecular Therapy in Haematology and Oncology & Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Tomska
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Young
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: III Medical Department, Technische Universität München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Keller
authors.affiliation: Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany.
authors.forename: Halvard
authors.initials: H
authors.lastname: Bönig
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.affiliation: Institute of Pathology, University of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.|Bioanalytics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.|German Cancer Consortium/ German Cancer Research Center, Heidelberg, Germany.
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Molecular Therapy in Haematology and Oncology & Department of Translational Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany.|German Cancer Consortium/ German Cancer Research Center, Heidelberg, Germany.|Department of Medicine V, Heidelberg University Medical Center, Heidelberg, Germany; and.|European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt, Germany.|Department of Haematology, University of Cambridge, Cambridge, United Kingdom.|Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Stem Cell Institute, Cambridge, United Kingdom.|German Cancer Consortium/ German Cancer Research Center, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D015514:Oncogene Proteins, Fusion; D011947:Receptors, Antigen, B-Cell; C000588904:TEL-Syk fusion protein, human; D000072377:Syk Kinase