Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis
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Stefanie Schlager1, Carina Salomon1, Sabine Olt1, Christoph Albrecht1, Anja Ebert2, Oliver Bergner1, Johannes Wachter1, Francesca Trapani1, Daniel Gerlach1, Tilman Voss1, Anna Traunbauer2, Julian Jude2, Matthias Hinterndorfer2, Martina Minnich2, Norbert Schweifer1, Sophia M. Blake1,3, Vittoria Zinzalla1, Barbara Drobits1, Darryl B. McConnell1, Norbert Kraut1, Mark Pearson1, Johannes Zuber2,4 and Manfred Koegl1
1 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
2 Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), Vienna, Austria
3 Current address: AstraZeneca AB, Gothenburg, Sweden
4 Medical University of Vienna, Vienna BioCenter (VBC), Vienna, Austria
Keywords: BCL6; DLBCL; lymphoma; inducible CRISPR/Cas9;
Received: May 24, 2019 Accepted: February 08, 2020 Published: March 03, 2020
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphomas worldwide and is characterized by a high diversity of genetic and molecular alterations. Chromosomal translocations and mutations leading to deregulated expression of the transcriptional repressor BCL6 occur in a significant fraction of DLBCL patients. An oncogenic role of BCL6 in the initiation of DLBCL has been shown as the constitutive expression of BCL6 in mice recapitulates the pathogenesis of human DLBCL. However, the role of BCL6 in tumor maintenance remains poorly investigated due to the absence of suitable genetic models and limitations of pharmacological inhibitors. Here, we have utilized tetracycline-inducible CRISPR/Cas9 mutagenesis to study the consequences of BCL6 deletion in established DLBCL models in culture and in vivo. We show that BCL6 knock-out in SU-DHL-4 cells in vitro results in an anti-proliferative response 4–7 days after Cas9 induction that was characterized by cell cycle (G1) arrest. Conditional BCL6 deletion in established DLBCL tumors in vivo induced a significant tumor growth inhibition with initial tumor stasis followed by slow tumor growth kinetics. Our findings support a role of BCL6 in the maintenance of lymphoma growth and showcase the utility of inducible CRISPR/Cas9 systems for probing oncogene addiction.
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