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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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			Action	DRS
	SRR7769354_1.fastq.gz	Fastqsanger.gz
	SRR7769354_2.fastq.gz	Fastqsanger.gz
	SRR7769355_1.fastq.gz	Fastqsanger.gz
	SRR7769355_2.fastq.gz	Fastqsanger.gz
	SRR7769356_1.fastq.gz	Fastqsanger.gz

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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 μ (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

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

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 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

B cell Lymphomas present Immunoglobulin Neoantigens

Project description:Immunoglobulin gene rearrangement and somatic hypermutation have the potential to create neoantigens in non-Hodgkin B cell lymphoma. However, the presentation of these putative immunoglobulin neoantigens by B cell lymphomas has not been proven. We used MHC immunoprecipitation followed by liquid chromatography and tandem mass spectrometry (LC-MS/MS) to define antigens presented by follicular lymphomas (FL), chronic lymphocytic leukemias (CLL), diffuse large B cell lymphoma (DLBCL) and mantle cell lymphomas (MCL). We found presentation of the clonal immunoglobulin molecule, including neoantigens by both class I and class II MHC, though more commonly in class II MHC. To determine whether B cell activation could promote presentation of immunoglobulin neoantigens, we used a toll-like receptor 9 (TLR9) agonists to upregulate expression of MHC-II. This resulted in enhanced class II MHC presentation of the immunoglobulin variable region including neoantigens. These findings demonstrate that immunoglobulin neoantigens are presented across most subtypes of B cell lymphomas. Activation of lymphoma cells to upregulate antigen presentation boosts presentation of immunoglobulin neoantigens and represents a strategy for augmenting lymphoma immunotherapies.

2019-01-07 | PXD010808 | Pride

Aeromonas hydrophila E2 strain:E2

Project description:Aeromonas hydrophila E2 strain:E2 Genome sequencing

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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

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

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