title: Elucidation of tonic and activated B-cell receptor signaling in Burkitt's lymphoma provides insights into regulation of cell survival.
abstract: Burkitt's lymphoma (BL) is a highly proliferative B-cell neoplasm and is treated with intensive chemotherapy that, because of its toxicity, is often not suitable for the elderly or for patients with endemic BL in developing countries. BL cell survival relies on signals transduced by B-cell antigen receptors (BCRs). However, tonic as well as activated BCR signaling networks and their relevance for targeted therapies in BL remain elusive. We have systematically characterized and compared tonic and activated BCR signaling in BL by quantitative phosphoproteomics to identify novel BCR effectors and potential drug targets. We identified and quantified ∼16,000 phospho-sites in BL cells. Among these sites, 909 were related to tonic BCR signaling, whereas 984 phospho-sites were regulated upon BCR engagement. The majority of the identified BCR signaling effectors have not been described in the context of B cells or lymphomas yet. Most of these newly identified BCR effectors are predicted to be involved in the regulation of kinases, transcription, and cytoskeleton dynamics. Although tonic and activated BCR signaling shared a considerable number of effector proteins, we identified distinct phosphorylation events in tonic BCR signaling. We investigated the functional relevance of some newly identified BCR effectors and show that ACTN4 and ARFGEF2, which have been described as regulators of membrane-trafficking and cytoskeleton-related processes, respectively, are crucial for BL cell survival. Thus, this study provides a comprehensive dataset for tonic and activated BCR signaling and identifies effector proteins that may be relevant for BL cell survival and thus may help to develop new BL treatments.
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany;
authors.forename: Jasmin
authors.initials: J
authors.lastname: Corso
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany;
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Pan
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany;
authors.forename: Roland
authors.initials: R
authors.lastname: Walter
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany;
authors.forename: Carmen
authors.initials: C
authors.lastname: Doebele
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany;
authors.forename: Sebastian
authors.initials: S
authors.lastname: Mohr
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, 37075 Goettingen, Germany;
authors.forename: Hanibal
authors.initials: H
authors.lastname: Bohnenberger
authors.affiliation: Institute of Pathology, University Medical Center Göttingen, 37075 Goettingen, Germany;
authors.forename: Philipp
authors.initials: P
authors.lastname: Ströbel
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany; Bioanalytics, Institute for Clinical Chemistry, University Medical Center Göttingen, 37075 Goettingen, Germany;
authors.forename: Christof
authors.initials: C
authors.lastname: Lenz
authors.affiliation: Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Mikolaj
authors.initials: M
authors.lastname: Slabicki
authors.affiliation: Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Department of Haematology, Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom;
authors.forename: Federico
authors.initials: F
authors.lastname: Comoglio
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium/German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rieger
authors.affiliation: Molecular Therapy in Hematology and Oncology, Department of Translational Oncology, National Center for Tumor Diseases, 69120 Heidelberg, Germany; German Cancer Research Center, 69120 Heidelberg, Germany; Department of Medicine V, Heidelberg University Medical Center, 69120 Heidelberg, Germany; European Molecular Biology Laboratory, 69117 Heidelberg, Germany;
authors.forename: Thorsten
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Goettingen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wienands
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Goettingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Engelke
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany; German Cancer Consortium/German Cancer Research Center, 69120 Heidelberg, Germany;
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.affiliation: Bioanalytical Mass Spectrometry Group, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany; Bioanalytics, Institute for Clinical Chemistry, University Medical Center Göttingen, 37075 Goettingen, Germany; henning.urlaub@mpibpc.mpg.de Thomas.Oellerich@kgu.de.
authors.forename: Henning
authors.initials: H
authors.lastname: Urlaub
authors.affiliation: Hematology/Oncology, Department of Medicine, Johann Wolfgang Goethe University, 60590 Frankfurt, Germany; Department of Haematology, Cambridge Institute of Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom; German Cancer Consortium/German Cancer Research Center, 69120 Heidelberg, Germany; henning.urlaub@mpibpc.mpg.de Thomas.Oellerich@kgu.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Oellerich
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011947:Receptors, Antigen, B-Cell
keywords: B-cell receptor; cancer biology; lymphoma; phosphoproteome