AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis

Description: 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

Homo sapiens

Multispecies

Mus musculus

Subject(s)

Cytidine Deaminase

Germinal Center

Lymphoma, Large B-Cell, Diffuse

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: Teater M, Dominguez P, Redmond D, et al. AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis. Nature Communications. 2018; 9:222.
Data Type: Genomic
Equipment Used: Illumina HiSeq 2000
High throughput gene sequencing system

Illumina HiSeq 2500
High throughput sequencing system
Software Used: SRA Toolkit
The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.
Dataset Format(s): Plain Text, SRA
Data Tool(s): RNA Seq

Bisulfite-Seq
Dataset Size: 991.8 MB (TAR of TXT), 336.3 GB (SRA)

Data Catalog Record Updated: 2023-12-07