title: Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin lymphoma.
abstract: Classical Hodgkin lymphoma (cHL), although originating from B cells, is characterized by the virtual lack of gene products whose expression constitutes the B-cell phenotype. Epigenetic repression of B-cell-specific genes via promoter hypermethylation and histone deacetylation as well as compromised expression of B-cell-committed transcription factors were previously reported to contribute to the lost B-cell phenotype in cHL. Restoring the B-cell phenotype may not only correct a central malignant property, but it may also render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted a high-throughput pharmacological screening based on >28 000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote reexpression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of 2 of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the antileukemia agents all-trans retinoic acid and arsenic trioxide (ATO) were found to reconstitute the silenced B-cell transcriptional program and reduce viability of cHL cell lines. When applied in combination with a screening-identified chemical, ATO evoked reexpression of the CD20 antigen, which could be further therapeutically exploited by enabling CD20 antibody-mediated apoptosis of cHL cells. Furthermore, restoration of the B-cell phenotype also rendered cHL cells susceptible to the B-cell non-Hodgkin lymphoma-tailored small-compound inhibitors ibrutinib and idelalisib. In essence, we report here a conceptually novel, redifferentiation-based treatment strategy for cHL.
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Center of Cancer Research, Binzhou Medical University Hospital, Binzhou, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Screening Unit, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Neuenschwander
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: J Henry M
authors.initials: JH
authors.lastname: Däbritz
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Nina-Rosa
authors.initials: NR
authors.lastname: Neuendorff
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Kolja
authors.initials: K
authors.lastname: Schleich
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Aitomi
authors.initials: A
authors.lastname: Bittner
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Milanovic
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Beuster
authors.affiliation: Screening Unit, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Radetzki
authors.affiliation: Screening Unit, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Specker
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Maurice
authors.initials: M
authors.lastname: Reimann
authors.affiliation: Institute for Molecular Tumor Biology, Westfälische Wilhelms-Universität, Münster, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Rosenbauer
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Mathas
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Lohneis
authors.affiliation: Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany; and.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hummel
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Dörken
authors.affiliation: Screening Unit, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: von Kries
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.
authors.forename: Soyoung
authors.initials: S
authors.lastname: Lee
authors.affiliation: Medical Department of Hematology, Oncology, and Tumor Immunology, and Molekulares Krebsforschungszentrum, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Max-Delbrück-Center for Molecular Medicine, Helmholtz Association, Berlin, Germany.|Berlin Institute of Health, Berlin, Germany.
authors.forename: Clemens A
authors.initials: CA
authors.lastname: Schmitt
mesh_terms: D018941:Antigens, CD19 / Q000276:immunology; D018951:Antigens, CD20 / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D057166:High-Throughput Screening Assays; D006689:Hodgkin Disease / Q000276:immunology*; D006801:Humans; D010641:Phenotype; D016133:Polymerase Chain Reaction; D059467:Transcriptome / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D018941:Antigens, CD19; D018951:Antigens, CD20; D000970:Antineoplastic Agents; C000604811:CD19 molecule, human