Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis
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// Stefanie Schlager 1 , Carina Salomon 1 , Sabine Olt 1 , Christoph Albrecht 1 , Anja Ebert 2 , Oliver Bergner 1 , Johannes Wachter 1 , Francesca Trapani 1 , Daniel Gerlach 1 , Tilman Voss 1 , Anna Traunbauer 2 , Julian Jude 2 , Matthias Hinterndorfer 2 , Martina Minnich 2 , Norbert Schweifer 1 , Sophia M. Blake 1 , 3 , Vittoria Zinzalla 1 , Barbara Drobits 1 , Darryl B. McConnell 1 , Norbert Kraut 1 , Mark Pearson 1 , Johannes Zuber 2 , 4 and Manfred Koegl 1 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 Correspondence to: Manfred Koegl, email: manfred.koegl@boehringer-ingelheim.com Keywords: BCL6; DLBCL; lymphoma; inducible CRISPR/Cas9; in vivo xenograft Received: May 24, 2019 Accepted: February 08, 2020 Published: March 03, 2020 ABSTRACT 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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BI-3802 surpassed the efficacy of non-degrading BCL6 inhibitors such as BI-3812 or PROTAC-based BCL6 degraders, which had only shown modest pre-clinical success.
“surpassing the efficacy of non-degrading Bcl6 inhibitors such as Bi-3812 or PROtAc-based Bcl6 degraders, which had only shown modest pre-clinical success (Mccoull et al. 2018;Schlager et al. 2020).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Schlager et al. 2020
The Introduction (page unavailable) says BI-3802 and similar BCL6 degraders generally had greater anti-proliferative activity in cultured cells than BCL6 inhibitors. It does not identify BI-3812, compare BI-3802 with PROTAC-based degraders, or characterize those alternatives as having only modest pre-clinical success. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAnti-proliferative effects of BI-3802 in lymphoma models closely mirrored genetic BCL6 deletion.
“the anti-proliferative effects observed in lymphoma models closely mirrored genetic BCL6 deletion”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Schlager et al. 2020
Knock-out of BCL6 in lymphoma cells results in tumor stasis.
“As expected, knock-out of BCL6 in lymphoma cells results in tumor stasis21.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [21]
BI-3802 induces rapid ubiquitination and degradation of BCL6.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [21]
BI-3802 results in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [21]
The effects of BI-3802 are comparable to a genetic knock-out and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders.
“BI-3802 induces rapid ubiquitination and degradation of BCL6, resulting in profound de-repression of BCL6 target genes and anti-proliferative effects in DLBCL cell lines, comparable to a genetic knock-out21, and superior to non-degrading BCL6 inhibitors such as BI-3812 or heterobifunctional BCL6 degraders5,6.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [21]
The antiproliferative and transcriptional effect of BI-3802 is comparable to knock-out of BCL6 using an inducible CRISPR-Cas9 system.
“In fact, the antiproliferative and transcriptional effect of BI-3802 is comparable to knock-out of BCL6 using an inducible CRISPR-Cas9 system21.”
From Small-molecule-induced polymerization triggers degradation of BCL6 (2020) · cites this paper as [21]
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References 49 · Cited by 36
- Authors
- Schlager, S., Salomon, C., Olt, S., Albrecht, C., Ebert, A., Bergner, O., Wachter, J., Trapani, F., Gerlach, D., Voss, T., Traunbauer, A., Jude, J., Hinterndorfer, M., Minnich, M., Schweifer, N., Blake, S. M., Zinzalla, V., Drobits, B., McConnell, D. B., Kraut, N., Pearson, M., Zuber, J., & Koegl, M.
- Affiliations
- Boehringer Ingelheim (Austria) (AT)
- Research Institute of Molecular Pathology (AT)
- Corresponding author
- Koegl, Manfred
- ORCID
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2020-03-03
- Volume
- 11
- Issue
- 9
- Pages
- 875-890
- ISSN
- 1949-2553 (ISSN-L)
- PMC
- PMC7061739
- OpenAlex
- W3009068954
- Cited by
- 36
- References
- 49
- Citations by year
- 2025: 8 · 2024: 6 · 2023: 7 · 2022: 8 · 2021: 6 · 2020: 1
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Licence
- cc-by
- Locations
- Oncotarget (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Austrian Science Fund (F4710)
- Wirtschaftsagentur Wien
- FP7 Ideas: European Research Council (336860)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- BCL6, diffuse large B-cell lymphoma, CRISPR/Cas9 mutagenesis, tetracycline-inducible expression, tumor maintenance, xenografts, transcriptional repressor, non-Hodgkin lymphoma, apoptosis
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