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Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin's lymphoma

Item Type:Article
Title:Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin's lymphoma
Creators Name:Du, J. and Neuenschwander, M. and Yu, Y. and Daebritz, J.H.M. and Neuendorff, N.R. and Schleich, K. and Bittner, A. and Milanovic, M. and Beuster, G. and Radetzki, S. and Specker, E. and Reimann, M. and Rosenbauer, F. and Mathas, S. and Lohneis, P. and Hummel, M. and Doerken, B. and von Kries, J.P. and Lee, S. and Schmitt, C.A.
Abstract:Classical Hodgkin's 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 render cHL susceptible to clinically established antibody therapies targeting B-cell surface receptors or small compounds interfering with B-cell receptor signaling. We conducted now a high-throughput pharmacological screening based on more than 28,000 compounds in cHL cell lines carrying a CD19 reporter to identify drugs that promote re-expression of the B-cell phenotype. Three chemicals were retrieved that robustly enhanced CD19 transcription. Subsequent chromatin immunoprecipitation-based analyses indicated that action of two of these compounds was associated with lowered levels of the transcriptionally repressive lysine 9-trimethylated histone H3 mark at the CD19 promoter. Moreover, the anti-leukemia 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 re-expression 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's lymphoma-tailored small compound inhibitors Ibrutinib and Idelalisib. In essence, we report here a conceptually novel, re-differentiation-based treatment strategy for cHL.
Keywords:Antineoplastic Agents, B-Lymphocytes, CD20 Antigens, Cell Differentiation, Chromatin Immunoprecipitation, Cultured Tumor Cells, Flow Cytometry, High-Throughput Screening Assays, Hodgkin Disease, Phenotype, Polymerase Chain Reaction, Transcriptome
Source:Blood
ISSN:0006-4971
Publisher:American Society of Hematology (U.S.A.)
Volume:129
Number:1
Page Range:71-81
Date:12 January 2017
Official Publication:https://doi.org/10.1182/blood-2016-02-700773
PubMed:View item in PubMed

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