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Regulation of normal B cell differentiation and malignant B cell survival by OCT2

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

OTHER RELATED OMICS DATASETS IN: PRJNA315886PRJNA315967PRJNA315965

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE79482 | GEO | 2016/05/25

SECONDARY ACCESSION(S): PRJNA315965

REPOSITORIES: GEO

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Regulation of normal B-cell differentiation and malignant B-cell survival by OCT2.

Project description:The requirement for the B-cell transcription factor OCT2 (octamer-binding protein 2, encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse, but their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This finding led us to examine the role of OCT2 in germinal center-derived lymphomas. shRNA knockdown showed that almost all diffuse large B-cell lymphoma (DLBCL) cell lines are addicted to the expression of OCT2 and its coactivator OCA-B. Genome-wide chromatin immunoprecipitation (ChIP) analysis and gene-expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL-10, ELL2, XBP1, MYC, TERT, and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies and a recurrent mutation of threonine 223 in the DNA-binding domain of OCT2. This neomorphic mutation subtly alters the DNA-binding preference of OCT2, leading to the transactivation of noncanonical target genes including HIF1a and FCRL3 Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface, we reveal a requirement for this protein-protein interface that ultimately might be exploited therapeutically. Our findings, combined with the predominantly B-cell-restricted expression of OCT2 and the absence of a systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL while avoiding systemic toxicity.

| S-EPMC4833274 | biostudies-literature

Regulation of normal B cell differentiation and malignant B cell survival by OCT2 (expression)

Project description:The requirement for the B cell transcription factor OCT2 (encoded by Pou2f2) in germinal center B cells has proved controversial. Here, we report that germinal center B cells are formed normally after depletion of OCT2 in a conditional knockout mouse but that their proliferation is reduced and in vivo differentiation to antibody-secreting plasma cells is blocked. This led us to examine the role of OCT2 in germinal center derived lymphomas. ShRNA knockdown showed that almost all DLBCL cell lines are addicted to the expression of OCT2 and its co-activator OCA-B. Genome-wide chromatin Immunoprecipitation analysis and gene expression profiling revealed the broad transcriptional program regulated by OCT2 that includes the expression of STAT3, IL10, ELL2, XBP1, MYC, TERT and ADA. Importantly, genetic alteration of OCT2 is not a requirement for cellular addiction in DLBCL. However, we detected amplifications of the POU2F2 locus in DLBCL tumor biopsies as well as a recurrent mutation of threonine 223 in the DNA binding domain of OCT2. This neomorphic mutation subtly alters the DNA binding preference of OCT2 leading to the transactivation of novel target genes including HIF1a and FCRL3. Finally, by introducing mutations designed to disrupt the OCT2-OCA-B interface we reveal a requirement for this protein-protein interface that might ultimately be exploited therapeutically. Our findings, combined with the predominantly B cell restricted expression of OCT2 and the absence of systemic phenotype in our knockout mice, suggest that an OCT2-targeted therapeutic strategy would be efficacious in both major subtypes of DLBCL whilst avoiding systemic toxicity.

2016-05-25 | GSE79292 | GEO

Regulation of normal B cell differentiation and malignant B cell survival by OCT2 (ChIP-Seq)

2016-05-25 | GSE79480 | GEO

Regulation of normal B cell differentiation and malignant B cell survival by OCT2

Project description:Regulation of normal B cell differentiation and malignant B cell survival by OCT2

| PRJNA315965 | ENA

Regulation of normal B cell differentiation and malignant B cell survival by OCT2 (expression)

Project description:Regulation of normal B cell differentiation and malignant B cell survival by OCT2 (expression)

| PRJNA315886 | ENA

Regulation of Mammalian Cell Growth and Survival By an RNA Polymerase II-Pausing Factor

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2011-08-17 | E-GEOD-24180 | biostudies-arrayexpress

Dose-dependent role of the cohesin complex in normal and malignant hematopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2015-09-21 | E-GEOD-73218 | biostudies-arrayexpress

Orchestrated intron retention regulates normal granulocyte differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-27 | E-GEOD-48307 | biostudies-arrayexpress

miR-99 regulates normal and malignant hematopoietic stem cell self-renewal

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

2017-07-27 | GSE101958 | GEO

Genomic Determinants of Gene Regulation by 1,25-Dihydroxyvitamin D3 During Osteoblast-Lineage Cell Differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-06-02 | E-GEOD-51515 | biostudies-arrayexpress

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