BCL6 BTB‐specific inhibitor reversely represses T‐cell activation, Tfh cells differentiation, and germinal center reaction in vivo

Cai, Yanhui; Reddy, Poli Adi Narayana; Vadrevu, Surya Kumari; Gyampoh, Kwasi; Hart, Colin; Ross, Brian N.; Fair, Matt; Xue, Fengtian; Salvino, Joseph M.; Montaner, Luis J.

doi:10.1002/eji.202049150

Cited by 6 publications

(4 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Long-term treatment was not possible due to the intraperitoneal route of drug administration, and better delivery systems need to be developed. Notably, FX1 was recently shown to alter Tfh-GC responses to sheep RBC injection and lymphoid hyperplasia in mice as well as a short-term nonhuman primate study [ 46 , 47 ]. However, if approaches such as these were to be employed for treatment options in autoimmune diseases, studies would need to be conducted to establish their safety and interference with the host-immunity to infectious diseases or response to immunizations.…”

Section: Discussionmentioning

confidence: 99%

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T‐follicular helper cells and germinal center B cells

et al. 2022

View full text Add to dashboard Cite

The Three Prime Repair EXonuclease I (TREX1) is critical for degrading post-apoptosis DNA. Mice expressing catalytically inactive TREX1 (TREX1 D18N) develop lupus-like autoimmunity due to chronic sensing of undegraded TREX1 DNA substrates, production of the inflammatory cytokines, and the inappropriate activation of innate and adaptive immunity. This study aimed to investigate Thelper (Th) dysregulation in the TREX1 D18N model system as a potential mechanism for lupus-like autoimmunity. Comparison of immune cells in secondary lymphoid organs, spleen and peripheral lymph nodes (LNs) between TREX1 D18N mice and the TREX1 null mice revealed that the TREX1 D18N mice exhibit a Th1 bias. Additionally, the T-follicular helper cells (Tfh) and the germinal celter (GC) B cells were also elevated in the TREX1 D18N mice. Targeting Bcl6, a lineage-defining transcription factor for Tfh and GC B cells, with a commercially available Bcl6 inhibitor, FX1, attenuated Tfh, GC, and Th1 responses, and rescued TREX1 D18N mice from autoimmunity. The study presents Tfh and GC B-cell responses as potential targets in autoimmunity and that Bcl6 inhibitors may offer therapeutic approach in TREX1-associated or other lupus-like diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T‐follicular helper cells and germinal center B cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Several small molecule inhibitors have been developed that target the BTB domain of BCL6 to block association with corepressors BCOR and NCOR/SMRT. These include BI-3812, 79-6, FX1, and the peptidomimetic RI-BPI 38, 50, 53, 54 . FX1 is a high potency derivative of 79-6.…”

Section: Resultsmentioning

confidence: 99%

BCL6 regulates the endothelial pro-immunogenic phenotype relevant to organ transplant rejection

Acevedo

Valenzuela

2022

Preprint

View full text Add to dashboard Cite

Background: IFNγ induces an endothelial cell pro-immunogenic phenotype through the JAK/STAT1 pathway, which can influence alloreactive leukocytes in transplant rejection. Numerous endogenous suppressors of JAK and STAT activation have been described, but regulation of STAT1 at the level of transcription is not well-understood. In immune cells, the DNA binding protein BCL6 controls transcription of lineage and inflammatory genes, including STAT-dependent responses. The goal of this study was to determine if BCL6 also modulates the IFNγ-induced immunogenic phenotype in endothelium. Methods: BCL6 binding to target genes and similarity to STAT1 motifs was analyzed in silico using public datasets. In vitro, primary human aortic endothelial cells were tested for expression of IFNγ-inducible costimulatory molecules, HLA and cytokines, under BCL6 overexpression, depletion and pharmacological targeting. Gene expression was measured by RNA-Seq and protein expression was confirmed by flow cytometry, Luminex and ELISA. Paired biopsies from stable and rejecting human cardiac allografts were compared for expression of BCL6, PD ligands, CXCL chemokines and HLA-DR in the vasculature. Results: BCL6 expression is increased within human cardiac transplants during rejection, which is positively correlated with expression of interferon response gene HLA-DR in donor blood vessels. Further, BCL6 is IFNγ-inducible via JAK1/2 in endothelium. Next, the consensus DNA binding motif of BCL6 is highly similar to that of STAT1, and numerous interferon response genes harbor BCL6 DNA binding motifs. Depletion of BCL6 in endothelium results in augmentation, while overexpression causes suppression, of MHC class II, chemokine, and PD ligand expression. Unexpectedly, pharmacological targeting of the corepressor domain BTB domain of BCL6 also repressed many interferon response genes, particularly HLA class II, CXCR3 chemokines and PD-L2. On the other hand, BCL6 targeting did not impact inducible expression of any HLA class I genes, PD-L1 or CD40; and the effect is correlated with the presence of BCL6 binding motifs in or near affected genes. Conclusion: Our results show for the first time that the transcriptional repressor BCL6 selectively controls the endothelial response to IFNγ. A better understanding of the endogenous mechanisms that regulate donor endothelial activation has the potential to discover new avenues to dampen transplant rejection, with broader relevance to other vascular inflammatory diseases.

show abstract

“…Based on the structure of 7 , 8 ( AP-4–287 ) was modified by an amino acid-based ester to work as a prodrug of 7 (Table ). There was a 150-fold increased solubility for 8 (218 ng/mL) compared to 7 (Scheme ). Furthermore, 8 could be quickly converted to 7 but exhibited a shorter half-life in mouse plasma.…”

Section: Recent Developments In Bcl6 Inhibitorsmentioning

confidence: 99%

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

et al. 2022

J. Med. Chem.

View full text Add to dashboard Cite

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that regulates the differentiation of B lymphocytes and mediates the formation of germinal centers (GCs) by recruiting corepressors through the BTB domain of BCL6. Physiological processes regulated by BCL6 involve cell activation, differentiation, DNA damage, and apoptosis. BCL6 is highly expressed when the gene is mutated, leading to the malignant proliferation of cells and drives tumorigenesis. BCL6 overexpression is closely correlated with tumorigenesis in diffuse large B-cell lymphoma (DLBCL) and other lymphomas, and BCL6 inhibitors can effectively inhibit some lymphomas and overcome resistance. Therefore, targeting BCL6 might be a promising therapeutic strategy for treating lymphomas. Herein, we comprehensively review the latest development of BCL6 inhibitors in diffuse large B-cell lymphoma and discuss the overview of the pharmacophores of BCL6 inhibitors and their efficacies in vitro and in vivo. Additionally, the current advances in BCL6 degraders are provided.

show abstract

BCL6 BTB‐specific inhibitor reversely represses T‐cell activation, Tfh cells differentiation, and germinal center reaction in vivo

Cited by 6 publications

References 32 publications

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T‐follicular helper cells and germinal center B cells

Targeting Bcl6 in the TREX1 D18N murine model ameliorates autoimmunity by modulating T‐follicular helper cells and germinal center B cells

BCL6 regulates the endothelial pro-immunogenic phenotype relevant to organ transplant rejection

B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

Contact Info

Product

Resources

About