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RNA-seq analysis of the effects of BCL6-inhibiting and BCL6-degrading compounds in lymphoma cell lines

ABSTRACT: The goal of this experiment is to measure the changes in gene expression induced by small molecules that either inhibit the interaction of the transcription factor BCL6 with co-repressor proteins, or that induce degradation of BCL6, in lymphoma cell lines.

ORGANISM(S): Homo sapiens

PROVIDER: GSE94099 | GEO | 2017/09/17

SECONDARY ACCESSION(S): PRJNA368848

REPOSITORIES: GEO

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PRMT5 Interacts with the BCL6 Oncoprotein and is Required for Germinal Center Formation and Lymphoma Cell Survival

Project description:We have found that PRMT5 methylates BCL6 and is needed for its full transcriptional repressor activity. Concomitant inhibition of both BCL6 and PRMT5 exhibits synergistic killing of BCL6-expressing lymphoma cells.

2018-12-06 | GSE116963 | GEO

Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

Project description: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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Frequent mutations of FBXO11 identify BCL6 as a therapeutic target in Burkitt Lymphoma

Project description:BCL6 is a key oncogene in lymphoma pathogenesis. The expression of BCL6 in lymphoid cells can be deregulated by several mechanisms, including chromosomal translocations, somatic mutations in the promoter regulatory regions or reduced proteasome-mediated degradation. FBXO11 was recently identified as a major ubiquitin ligase involved in the degradation of BCL6 and is frequently inactivated in diffuse large B-cell lymphoma (DLBCL). In this work, we found that FBXO11 is frequently mutated in Burkitt lymphoma (BL) but rarely mutated in other BCL6-positive lymphomas, such as follicular lymphoma (FL). All mutations tested impaired FBXO11 mediated BCL6 degradation and FBXO11 knock-out completely stabilized BCL6 levels in human BL cell lines. Conditional deletion of one copy or both copies of FBXO11 in c-Myc-driven B cell lymphoma in mice accelerated lymphomagenesis, genetically confirming that FBXO11 is a haplo-insufficient oncosuppressor in lymphoma. In both FBOX11 WT and deficient BL mouse and human cell lines, blockade of BCL6 via a specific degrader or BCL6 inhibitors, impaired lymphoma growth in vitro and in vivo, an effect further enhanced by co-inhibition of c-Myc activity. Overall these findings not only establish FBXO11 as one of the most frequently mutated genes in BL, but also elucidate its biological functions in lymphomagenesis and thereby identify BCL6 as a specific therapeutic target in BL.

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Bcl6

Project description:Rattus norvegicus Bcl6, BCL6, transcription repressor [Source:RGD Symbol;Acc:1309345], is expressed in 5 baseline experiment(s);

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BCL6

Project description:Sus scrofa BCL6, BCL6 transcription repressor [Source:VGNC Symbol;Acc:VGNC:96565], is differentially expressed in 6 experiment(s);

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Project description:Macaca mulatta BCL6, BCL6 transcription repressor [Source:VGNC Symbol;Acc:VGNC:70036], is expressed in 3 baseline experiment(s);

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Project description:Oryctolagus cuniculus BCL6, BCL6 transcription repressor [Source:HGNC Symbol;Acc:HGNC:1001], is expressed in 1 baseline experiment(s);

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