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SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis

ABSTRACT: SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis

PROVIDER: PRJNA784920 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17074006_1.fastq.gz	Fastqsanger.gz
	SRR17074006_2.fastq.gz	Fastqsanger.gz
	SRR17074007_1.fastq.gz	Fastqsanger.gz
	SRR17074007_2.fastq.gz	Fastqsanger.gz
	SRR17074008_1.fastq.gz	Fastqsanger.gz

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SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis

Project description:SETD2 is the sole chromatin modifier responsible for H3K36me3, a histone mark linked to splicing, transcription initiation and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is virtually always heterozygous in diffuse large B-cell lymphomas (DLBCL). Here we show that heterozygous SETD2 deficiency results in germinal center (GC) hyperplasia and accelerated lymphomagenesis. SETD2 haploinsufficient GC B-cells exhibit increased competitive fitness and reduced DNA damage checkpoint activity, resulting in decreased apoptosis. SETD2 haploinsufficient GCB and lymphoma cells featured increased off- and on-target AICDA induced somatic hypermutation (SHM), complex structural variants such as rygma, and increased translocations including those activating MYC. DNA damage was selectively increased on the non-template strand and H3K36me3 loss was associated with greater RNA Pol II processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination during transcription. Hence, SETD2 haploinsufficiency delineates a novel GC B-cell context specific oncogenic pathway involving defective epigenetic surveillance of AICDA mediated somatic hypermutation induced off target effects on transcribed genes.

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Project description:SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B cell lymphomagenesis

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AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

Project description:AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

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AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

Project description:Epigenetic heterogeneity is emerging as a significant phenotypic feature of tumors. In diffuse large B-cell lymphomas (DLBCLs), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the biological mechanisms driving epigenetic heterogeneity remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that deaminates and facilitates demethylation of DNA methyl-cytosines in germinal center (GC) B-cells, is required for DLBCL pathogenesis and linked to inferior clinical outcomes. Here, we show that overexpression of AICDA causes more aggressive disease and worse outcome in BCL2-driven murine lymphomas. This phenotype was associated with significantly increased focal inter-tumor and intra-tumor cytosine methylation heterogeneity as compared to control lymphomas, but not with increased mutational burden. AICDA-mediated epigenetic heterogeneity was accompanied by DNA hypomethylation. Reciprocally, we observed that the focal inter-individual and intra-individual cytosine methylation heterogeneity characteristic of normal GC B-cells was lost upon depletion of AICDA. There was significant overlap of AICDA-induced methylation heterogeneity foci in GC B-cells and murine lymphomas. These observations are relevant to human patients, since DLBCLs with high AICDA expression likewise manifest extensive increases in focal inter-patient and intra-patient heterogeneity as compared to DLBCLs with low AICDA expression. Affected regions significantly overlapped with those found in murine AICDA-overexpressing lymphomas. Our results identify AICDA as a novel source of epigenetic plasticity and heterogeneity in B-cell lymphomas with potential significance for other tumors that express cytosine deaminases.

2018-01-19 | GSE95013 | GEO

Differential programming of B cells in Aicda-/- mice [MethylCap-Seq]

Project description:We determined CpG methylation load from GC B cells obtained from both Aicda-/- and Aicda+/+ mice. Examination of methylation load of Aicda-/- and Acida+/+ GC B cells.

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Differential programming of B cells in Aicda-/- mice [RNA-Seq]

Project description:We sequenced mRNA from naive, in vitro activated, and GC B cells obtained from both Aicda-/- and Aicda+/+ mice. Examination of mRNA levels in naive, in vitro activated, and GC B cells.

2013-06-07 | E-GEOD-47703 | biostudies-arrayexpress

Differential programming of B cells in Aicda-/- mice [MethylCap-Seq]

Project description:We determined CpG methylation load from GC B cells obtained from both Aicda-/- and Aicda+/+ mice.

2013-06-07 | GSE47704 | GEO

Differential programming of B cells in Aicda-/- mice [RNA-Seq]

Project description:We sequenced mRNA from naive, in vitro activated, and GC B cells obtained from both Aicda-/- and Aicda+/+ mice.

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Independent roles of switching and hypermutation in the development and persistence of B lymphocyte memory [Nurr77]

Project description:Somatic hypermutation (SHM) and class switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system.

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