AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA375214 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5264520.fastq.gz | Fastqsanger.gz | |||
| SRR5264530_1.fastq.gz | Fastqsanger.gz | |||
| SRR5264530_2.fastq.gz | Fastqsanger.gz | |||
| SRR5264540_1.fastq.gz | Fastqsanger.gz | |||
| SRR5264540_2.fastq.gz | Fastqsanger.gz |
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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.
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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:Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.
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