A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

Cerchietti, Leandro; Ghetu, Alexandru F.; Zhu, Xiaohan; Silva, Gustavo F. Da; Zhong, Shijun; Matthews, Marilyn; Bunting, Karen; Polo, José M.; Farès, Christophe; Arrowsmith, C.H.; Yang, Shao Ning; Garcia, Monica; Coop, Andrew; MacKerell, Alexander D.; Privé, Gilbert G.; Melnick, Ari

doi:10.1016/j.ccr.2009.12.050

Cited by 263 publications

(275 citation statements)

References 50 publications

Supporting

Mentioning

270

Contrasting

Order By: Relevance

“…Next, we verified whether increased expression of CTLA-4 in T cells activated in the presence of the MR was indeed due to lack of Bcl-6 binding to the CTLA-4 promoter. Therefore, we activated T cells in the presence of a Bcl-6 inhibitor (25). Indeed, T cells activated in the absence of Bcl-6 activity showed a markedly increased expression of CTLA-4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The mannose receptor (MR) is an endocytic receptor involved in serum homeostasis and antigen presentation. Here, we identify the MR as a direct regulator of CD8 + T-cell activity. We demonstrate that MR expression on dendritic cells (DCs) impaired T-cell cytotoxicity in vitro and in vivo. This regulatory effect of the MR was mediated by a direct interaction with CD45 on the T cell, inhibiting its phosphatase activity, which resulted in up-regulation of cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4) and the induction of T-cell tolerance. Inhibition of CD45 prevented expression of B-cell lymphoma 6 (Bcl-6), a transcriptional inhibitor that directly bound the CTLA-4 promoter and regulated its activity. These data demonstrate that endocytic receptors expressed on DCs contribute to the regulation of T-cell functionality.T he mannose receptor (MR) is an endocytic receptor belonging to the C-type lectin family and is expressed by distinct populations of dendritic cells (DCs), macrophages, and endothelial cells (1). It consists of an N-terminal cysteine-rich domain (CR), a fibronectin type II (FN II) domain, eight C-type lectinlike domains (CTLDs), a transmembrane region, and a short intracellular region. The CTLDs of the MR can bind to glycoconjugates terminated in mannose, fucose, or glucose. Despite the presence of eight CTLDs, only CTLD4 is responsible for carbohydrate binding. Additionally, the MR can bind to sulfated carbohydrates via its CR and to collagen via its FN II domain (1).In a previous study, we demonstrated that antigens internalized by the MR are processed specifically for cross-presentation (2). The correlation between the MR and cross-presentation offered the possibility that antigens targeted toward the MR could induce potent cytotoxic T-cell responses. Because the induction of a strong cytotoxic T-cell response against tumor-specific antigens is a crucial process in many tumor vaccination strategies, antigen targeting toward the MR seemed to be a promising approach. However, in in vivo tumor models, antigen targeting toward the MR did not result in a strong cytotoxic T-cell response but, instead, led to the induction of antigen-specific T-cell tolerance (3, 4). Therefore, we analyzed whether the MR has a regulatory effect on the induction of immune responses by means distinct from antigen uptake and presentation, and we investigated a direct influence of the MR on T-cell activation. We could demonstrate that the presence of the MR on the antigen-presenting cell (APC) directly impairs the cytotoxic activity of T cells in vitro and in vivo. We showed that this effect was due to a direct interaction of the MR with CD45 on the T-cell surface. This interaction inhibited CD45 activity and resulted in the up-regulation of the inhibitory molecule cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4), which was responsible for the impaired cytotoxic activity of the T cells. ResultsThe Presence of the MR on DCs Reduces Cytotoxic Activity of CD8 + T Cells. To investigate whether the MR influences T-cell ...

show abstract

Section: Resultsmentioning

confidence: 99%

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Schuette

Embgenbroich

Ulas

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Tumor size was measured with sliding calipers in three dimensions every another day for 26 days and calculated according to the formula: volume (mm 3 ) ¼ (smallest diameter width 2 Â largest diameter length)/2. 28 When mice were euthanized, tumors were excised and weighed with an electronic balance, then fixed and stained with hematoxylin and eosin for morphological examination. Terminal transferase dUTP nick-end labeling staining was carried out using the In Situ Cell Death Detection Kit (Roche, Mannheim, Germany).…”

Section: Tumor Model In Nude Micementioning

confidence: 99%

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

et al. 2012

View full text Add to dashboard Cite

Transcriptional positive coactivator 4 (PC4) is a multifunctional nuclear protein that has important roles in DNA transcription, replication, repair and heterochromatinization. However, the role of PC4 in cancer remains to be clarified. Several studies propose that PC4 may act as a putative tumor suppressor. Here, we demonstrate for the first time that PC4 may represent a potential therapeutic target in non-small cell lung cancer (NSCLC). PC4 protein expression is significantly upregulated in NSCLC carcinoma tissues compared with their adjacent noncancerous counterparts as shown by immunohistochemical staining and western blotting in 104 pairs of formalin-fixed human NSCLC specimens and 6 fresh NSCLC samples. Knockdown of PC4 expression by sequence-specific small interfering RNA (siRNA) in human NSCLC cells (A549, H460 and H358) significantly inhibits the growth of cancer cells by the induction of cell cycle arrest and the increase of cell apoptosis in vitro. Interrupting the PC4 signaling pathway by injection of the PC4 siRNA liposome complex produced an effective regression of pre-established A549 cell xenografts in mice through growth inhibition and increased apoptosis. These results indicated that PC4 could be an attractive new therapeutic target for the treatment of NSCLC.

show abstract

“…Hence, the role of BCL6 as a regulator of cell survival and proliferation is principally mediated through the BTB domain and is mostly relevant to its physiological actions in GC B-cells (Figure 2). The same mechanism is maintained during tumorigenesis, as demonstrated by the fact that GC-derived lymphomas are sensitive to the BCL6 BTB inhibitors [14,15,49]. Unexpectedly, BTB loss of function did not result in significant impairment of Tfh cell development and function as well as aberrant differentiation of other T helper subtypes [16].…”

Section: The Bcl6 Btb Domain Is Critical For Proliferation and Survivmentioning

confidence: 73%

“…These different co-repressor complexes appear to suppress distinct gene sets, perhaps mediating different activities of BCL6 in various immune cells. This notion has been in part supported by studies using inhibitors that selectively disrupt the co-repressors binding to the BCL6 BTB (BR-C, ttk and bab) domain [14,15]. However, the link between the transcriptional mechanisms of action of BCL6 with its biological actions in the immune system remains to be further characterized.…”

mentioning

confidence: 71%

Mechanisms of action of BCL6 during germinal center B cell development

Huang

Melnick

2015

Sci. China Life Sci.

Self Cite

View full text Add to dashboard Cite

The transcriptional repressor B cell lymphoma 6 (BCL6) controls a large transcriptional network that is required for the formation and maintenance of germinal centers (GC). GC B cells represent the normal counterpart of most human B-cell lymphomas, which are often characterized by deregulated BCL6 expression or BCL6-mediated pathways. BCL6 suppresses gene transcription largely through recruitment of its co-repressors through its distinct repression domain. Understanding the precise biological roles of each repression domain in normal and malignant B cells is helpful for development of targeted inhibition of BCL6 functions that is emerging as the basis for design of anti-lymphoma therapies. This review focuses on recent progress in the molecular mechanisms of action of BCL6 in B cells and discusses remaining unresolved questions related to how these mechanisms are linked to normal and malignant B cell development. BCL6, germinal center, co-repressor, lymphoma Citation:Huang CX, Melnick A. Mechanisms of action of BCL6 during germinal center B cell development.

show abstract

A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo

Cited by 263 publications

References 50 publications

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4

Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer

Mechanisms of action of BCL6 during germinal center B cell development

Contact Info

Product

Resources

About