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Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in the activated B-cell subtype of diffuse large B-cell lymphoma.

ABSTRACT: Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in the activated B-cell subtype of diffuse large B-cell lymphoma.

PROVIDER: PRJNA489303 | ENA |

REPOSITORIES: ENA

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Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma.

Project description:The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin ? (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

| S-EPMC6724184 | biostudies-literature

Genome wide screening for binding of TCF4 (E2-2) transcription factor in ABC like diffuse large B-cell lymphoma line TMD8.

Project description:We identified potential TCF4 targeted genes by performing CHIP-Seq using TCF4 antibody in ABC like DLBCL cell lines. We have identified strong binding of TCF4 to enhancer elements of B-cell receptor signaling components which drives B-cell receptor signaling.

2019-04-18 | GSE119476 | GEO

Genome wide screening for binding of TCF4 (E2-2) transcription factor in SU-DHL-2 ABC like diffuse large B-cell lymphoma lines.

2019-04-18 | GSE119475 | GEO

Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in the activated B-cell subtype of diffuse large B-cell lymphoma.

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-04-18 | GSE119477 | GEO

Genome wide screening for binding of TCF4 (E2-2) transcription factor in ABC like diffuse large B-cell lymphoma line TMD8.

Project description:Genome wide screening for binding of TCF4 (E2-2) transcription factor in ABC like diffuse large B-cell lymphoma line TMD8.

| PRJNA489306 | ENA

Genome wide screening for binding of TCF4 (E2-2) transcription factor in SU-DHL-2 ABC like diffuse large B-cell lymphoma lines.

Project description:Genome wide screening for binding of TCF4 (E2-2) transcription factor in SU-DHL-2 ABC like diffuse large B-cell lymphoma lines.

| PRJNA489305 | ENA

Aeromonas hydrophila E2 strain:E2

Project description:Aeromonas hydrophila E2 strain:E2 Genome sequencing

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Complex Balanced Translocation Disrupting TCF4 and Altering TCF4 Isoform Expression Segregates as Mild Autosomal Dominant Intellectual Disability

Project description:Mutations of TCF4, which encodes a basic helix-loop-helix transcription factor, cause Pitt-Hopkins syndrome (PTHS) via multiple genetic mechanisms. TCF4 is a complex locus expressing multiple transcripts by alternative splicing and use of multiple promoters. We report a three-generation family segregating mild intellectual disability with an apparently balanced chromosomal translocation t(14;18)(q23.3;q21.2) that we characterized as a complex unbalanced karyotype 46,XY,der(14)del(14)(q23.3q23.3)t(14;18)(q23.3;q21.2)del(18)(q21.2q21.2) del(18)(q21.2q21.2)inv(18)(q21.2q21.2),der(18)t(14 ;18)(q23.3;q21.2) disrupting TCF4. Using whole genome sequencing, transcriptome sequencing, qRT-PCR and nCounter analysis, we characterized the breakpoint junctions from derivative chromosomes and gene expression at the TCF4 locus. Our analyses revealed that family members segregating mild intellectual disability with the complex chromosome aberration had normal expression of genes along chromosomes 14 or 18 and no marked changes in expression of genes other than TCF4. Affected individuals had 12-33 fold higher mRNA levels of TCF4 than did unaffected controls or individuals with PTHS. Increased levels of TCF4 transcript variants originating distal to the translocation breakpoint, not the fusion transcript generated by the derivative chromosome, contributed to this increased. Although validation in additional patients is required, our findings suggest that the dysmorphic features and severe intellectual disability characteristic of PTHS is partially rescued by overexpression of short TCF4 transcripts encoding a nuclear localization signal, a transcription activation domain, and the basic helix-loop-helix domain. Examination of TCF4 Isoform expression comparison between mutant and control skin fibroblast tissues

2016-05-31 | E-GEOD-77742 | biostudies-arrayexpress

Cytokine stimulated keratinocytes (TCF4 KD)

Project description:In order to study the molecular mechanisms involving TCF4 in keratinocytes under different inflammatory responses, control and TCF4 knock down keratinocytes were stimulated with inflammatory cytokines and conducted RNA-seq to profile the gene expression.

2024-06-05 | GSE260642 | GEO

TCF4 regulatory gene networks in developing dorsal telencephalon

Project description:Haplo-insufficiency of TCF4 induced by mutations or microdeletion of TCF4 gene causes Pitt-Hopkins Diseases. Recent gene association studies revealed that mutations of TCF4 is significantly associated with schizophrenia. But the role of TCF4 in developing neocortex is not known. The goal of this study is to identify TCF4 itranscriptional regulatory pathways in developing neocortex by analyzing transcriptomes of dorsal telencephalons of TCF4knockout, TCF4Heterozygote and WT littermates and comparing differential expressed genes between these genotypes.

2019-02-06 | GSE79663 | GEO

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