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Therapeutic targeting of GCB- and ABC-DLBCLs by rationally designed BCL6 inhibitors

ABSTRACT: BCL6 inhibitor induces derepression of BCL6 target genes and shows a similar transcriptional program to BCL6 siRNA

ORGANISM(S): Homo sapiens

PROVIDER: GSE79888 | GEO | 2016/10/13

SECONDARY ACCESSION(S): PRJNA317329

REPOSITORIES: GEO

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Therapeutic targeting of GCB- and ABC-DLBCL by rationally designed BCL6 inhibitor

Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.

2016-10-12 | GSE80351 | GEO

Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma.

Project description: Not available

| S-EPMC5004937 | biostudies-literature

BCL6 confers KRAS-mutant NSCLCs resistance to BET inhibitors [ChIP-Seq]

Project description:We report that BCL6 interacts with BRD3 and that BRD3 inhibition upregulates BCL6. By obtaining sequence from chromatin immunoprecipitated DNA of A549 cells, we generated genome-wide binding gene spectrums of BCL6 and BRD3. By locating -3000 to +200 bps around TSS, we find that BRD3 binds to the promoters of 2470 genes and that BCL6 binds to the promoters of 694 genes, with 82 genes shared by BRD3 and BCL6. Interestingly, BCL6 itself is one of these 82 shared genes, implying that BCL6 mediated self-repression may require the participation of BRD3. Other shared genes includes SGK2, IDH2, HOXB6, SIRT1, SOCS3 and ZFNs, demonstrating the widely involvement of BRD3 in the regulatory role of BCL6. To examine the dependency of BCL6 on BRD3, we also compared BCL6-binding spectrums with or without a BET inhibitor, OTX015. The ChIP-seq data with BCL6 antibody exhibited a diverse BCL-binding spectrum composed of 731 genes in OTX015 treatment, with only 117 genes overlapped with that of DMSO treatment. These data demonstrates that BET inhibition is sufficient to change BCL6-binding spectrum. This study provides a new insight of BCL6 regulatory roles in KRAS-mutant NSCLCs, where BRD3 is recruited by BCL6 and affect BCL6 binding preference as a cofactor.

2018-09-13 | GSE119863 | GEO

Rationally Designed Covalent BCL6 Inhibitor That Targets a Tyrosine Residue in the Homodimer Interface.

Project description: Not available

| S-EPMC7294706 | biostudies-literature

Inhibition of synucleinopathic seeding by rationally designed inhibitors.

Project description: Not available

| S-EPMC6977966 | biostudies-literature

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.

Project description: Not available

| S-EPMC3998711 | biostudies-literature

BCL6 enforces human glioblastoma growth and serves as a novel therapeutic target (expression)

Project description:ZBTB transcription factors extensively orchestrate gene transcription during tissue development. However, their roles in glioblastoma multiforme (GBM) remain largely unexplored. Here, through integrated functional screening and expression analyses of 49 human ZBTB genes, we identify that BCL6 is required for GBM cell proliferation and is overexpressed in GBM samples. High expression of BCL6 is associated with poor overall survival of GBM patients. Genome-wide occupancy analysis and transcriptome analysis demonstrates that BCL6 is recruited to the loci of various tumor-promoting genes (e.g. MYC, FOSL1, MALAT1 and NEAT1) and maintains their expression. Pathway enrichment analysis reveals that BCL6 regulates several important cancer related pathways (e.g. TP53, ErbB and MAPK signaling pathways). BCL6 represses the expression of TP53 and its target genes, CDKN1A and CDKN1B, thereby promoting GBM cell resistance to ionizing radiation. Moreover, antibody array profiling uncovers AXL and MET are selectively activated by BCL6 in GBM. Moreover, BCL6 enhances both MEKERK and S6K-RPS6 axes as well as cap-dependent translation through the induction of AXL expression. Importantly, depletion of BCL6 or pharmacological inhibition of BCL6/NCoR complex effectively blocks GBM growth both in vitro and in vivo, and sensitizes GBM cells to EGFR inhibitors. Together, these findings uncover a novel growth-promoting role of BCL6 in GBM, and provide the rationale of targeting BCL6 as a potential therapeutic approach for this deadly malignancy. cDNA microarray analysis was performed in U87 cells transfected with either non-targeting siRNAs or BCL6 siRNAs. All experiments were carried out in duplicates.

2016-08-01 | E-GEOD-77053 | biostudies-arrayexpress

Gene expression analysis of testicular DLBCL: ABC or GCB subtype?

Project description:Diffuse large B cell lymphomas (DLBCL) constitute a heterogeneous group of lymphomas in which germinal center B cell-like and activated B cell-like subtypes can be discerned based on pathology, clinical presentation and gene expression patterns. Testicular DLBCL form an immune-privileged site-related subgroup of DLBCL with an unfavorable prognosis. We used cDNA microarray analysis, immunohistochemistry for CD10, Bcl6 and MUM1, and somatic hypermutation analysis of the immunoglobulin heavy chain gene rearrangements to determine the subtype of primary testicular DLBCL. Immunohistochemistry revealed 14/22 testicular DLBCL with an activated B cell-like immunophenotype and 8/22 with an ambiguous immunophenotype co-expressing CD10 and high levels of MUM1. cDNA microarray analysis of these 22 and 4 additional cases showed a uniform activated B cell-like gene expression pattern in both immunophenotypes. Somatic hypermutation analysis showed a very high mutation load in 7 cases tested, but intraclonal heterogeneity was found at low level in only one of these cases. We conclude that primary testicular DLBCL have uniform activated B cell-like subtype characteristics despite a number of cases showing an ambiguous immunophenotype. Keywords: Gene expression

2006-05-01 | GSE4296 | GEO

Covalent Targeting of Ras G12C by Rationally Designed Peptidomimetics.

Project description: Not available

| S-EPMC7739374 | biostudies-literature

Targeting of REST with rationally-designed small-molecule compounds exhibits synergetic therapeutic potential in human glioblastoma cells

Project description:To validate role of REST (RE-1 silencing transcription factor) in glioblastoma (GBM) growth, we used CRISPR/Cas9 gene editing to generate REST-null single-cell clonal lines from GBM cell line (T98G) and non-neural HEK293 cells. We then performed gene expression profiling using data obtained from Tag-Seq of 8 cell lines: T98G CRISRP Control and 4 T98G REST-KO clones (C10, F7, G2, D4); HEK293 CRISPR Control and 2 HEK293 REST-KO clones (D10, E6).

2024-03-27 | GSE234912 | GEO

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