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

Jing Du, Martin Neuenschwander, Yong Yu, J. Henry M. Däbritz, Nina-Rosa Neuendorff, Kolja Schleich, Aitomi Bittner, Maja Milanovic, Gregor Beuster, Silke Radetzki, Edgar Specker, Maurice Reimann, Frank Rosenbauer, Stephan Mathas, Philipp Lohneis, Michael Hummel, Bernd Dörken, Jens Peter von Kries, Soyoung Lee and Clemens A. Schmitt

Key Points

  • A pharmacological screening identified compounds that reactivate B-cell–specific gene expression in cHL cell lines.

  • B-cell phenotype-restoring drug combinations render cHL cell lines susceptible to B-NHL–reminiscent targeted therapies.

Publisher's Note: There is an Inside Blood Commentary on this article in this issue.

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.

  • Submitted February 19, 2016.
  • Accepted September 23, 2016.
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