https://orcid.org/0000-0001-8164-7268
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ABSTRACT
Few recurrent DNA mutations are seen in aggressive canine B cell lymphomas (cBCL), suggesting other frequent drivers. The methylated island recovery assay (MIRA-seq) or methylated CpG-binding domain sequencing (MBD-seq) was used to define the genome-wide methylation profiles in aggressive cBCL in Golden Retrievers to determine if cBCL can be better defined by epigenetic changes than by DNA mutations. DNA hypermethylation patterns were relatively homogenous within cBCL samples in Golden Retrievers, in different breeds and in geographical regions. Aberrant hypermethylation is thus suspected to be a central and early event in cBCL lymphomagenesis. Distinct subgroups within cBCL in Golden Retrievers were not identified with DNA methylation profiles. In comparison, the methylome profile of human DLBCL (hDLBCL) is relatively heterogeneous. Only moderate similarity between hDLBCL and cBCL was seen and cBCL likely cannot be accurately classified into the subtypes seen in hDLBCL. Genes with hypermethylated regions in the promoter-TSS-first exon of cBCL compared to normal B cells often also had additional hyper- and hypomethylated regions distributed throughout the gene suggesting non-randomized repeat targeting of key genes by epigenetic mechanisms. The prevalence of hypermethylation in transcription factor families in aggressive cBCL may represent a fundamental step in lymphomagenesis.
Abbreviations
| ABC: activated B cells | = | |
| cBCL: canine aggressive B-cell lymphoma | = | |
| cDLBCL: canine diffuse large B-cell lymphoma | = | |
| CGI: CpG island | = | |
| CpG: cytosine-phospho-guanosine dinucleotide | = | |
| DMR: differentially methylated region | = | |
| GCB: germinal center B cells | = | |
| GEP: gene expression profiling | = | |
| GR: Golden Retriever | = | |
| hDLBCL: human diffuse large B-cell lymphoma | = | |
| hBCL: human aggressive B-cell lymphoma | = | |
| NHL: non-Hodgkin lymphoma | = | |
| PBMC: peripheral blood mononuclear cells | = | |
| TSS: transcription stop site | = | |
| TTS: transcription termination site | = | |
| UTR: untranslated region | = |
Acknowledgments
The authors would like to acknowledge Hans Rindt, Senthil Kumar, and Maren Fleer at the University of Missouri for technical assistance. The authors would like to acknowledge Obi L Griffith for bioinformatics assistance.
Data availability
Data was deposited into SRA under accession PRJNA808112.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15592294.2022.2105033
