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AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

UID: 10699

Summary from the GEO: "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."

Overall design from the GEO: "Enhanced reduced representation bisulfite sequencing (ERRBS), RNA-seq, and exome sequencing on murine VavP-Bcl2 and VavP-Bcl2+Aicda tumors. Enhanced reduced representation bisulfite sequencing (ERRBS), RNA-seq and exome sequencing on murine VavP-Bcl2 and VavP-Bcl2+Aicda tumors. Paired ERRBS and RNA-seq on low AICDA-expressing and high AICDA-expression DLBCL."
Subject of Study
OncoTree Cancer Type(s)
Diffuse Large B-Cell Lymphoma, NOS
High-Grade B-Cell Lymphoma, with MYC and BCL2 and/or BCL6 Rearrangements
Mature B-Cell Neoplasms
Access via GEO

Plain Text files of expression, methylation and genome variation profiling by high throughput sequencing
Accession #: GSE95013

Access via SRA

Bisulfite, RNA and Other Sequencing of 88 samples
Accession #: SRP100105

Access via BioProject

Additional information about the overall inititative.
Accession #: PRJNA375214

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications
Data Type
Equipment Used
Illumina HiSeq 2000
Illumina HiSeq 2500
Software Used
SRA Toolkit
Dataset Format(s)
Plain Text, SRA
Data Tool(s)
Dataset Size
991.8 MB (TAR of TXT), 336.3 GB (SRA)
Data Catalog Record Updated