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| Item Type: | Article |
|---|---|
| Title: | Pharmacological restoration and therapeutic targeting of the B-cell phenotype in classical Hodgkin's lymphoma |
| Creators Name: | Du, J., Neuenschwander, M., Yu, Y., Däbritz, J.H.M., Neuendorff, N.R., Schleich, K., Bittner, A., Milanovic, M., Beuster, G., Radetzki, S., Specker, E., Reimann, M., Rosenbauer, F., Mathas, S., Lohneis, P., Hummel, M., Dörken, B., von Kries, J.P., 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 |
| Volume: | 129 |
| Number: | 1 |
| Page Range: | 71-81 |
| Date: | 5 January 2017 |
| Additional Information: | Copyright © 2017 by The American Society of Hematology |
| Official Publication: | https://doi.org/10.1182/blood-2016-02-700773 |
| PubMed: | View item in PubMed |
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