Genome-wide detection of genes targeted by non-Ig somatic hypermutation in lymphoma.

TitleGenome-wide detection of genes targeted by non-Ig somatic hypermutation in lymphoma.
Publication TypeJournal Article
Year of Publication2012
AuthorsJiang Y, T Soong D, Wang L, Melnick AM, Elemento O
JournalPLoS One
Date Published2012
KeywordsB-Lymphocytes, Cell Differentiation, Cell Line, Tumor, Chromatin Immunoprecipitation, Gene Expression Regulation, Neoplastic, Genes, Neoplasm, Genes, Regulator, Genome, Human, Histones, Humans, Lymphoma, Lymphoma, Large B-Cell, Diffuse, Methylation, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Analysis, DNA, Somatic Hypermutation, Immunoglobulin

The processes of somatic hypermutation (SHM) and class switch recombination introduced by activation-induced cytosine deaminase (AICDA) at the Immunoglobulin (Ig) loci are key steps for creating a pool of diversified antibodies in germinal center B cells (GCBs). Unfortunately, AICDA can also accidentally introduce mutations at bystander loci, particularly within the 5' regulatory regions of proto-oncogenes relevant to diffuse large B cell lymphomas (DLBCL). Since current methods for genomewide sequencing such as Exon Capture and RNAseq only target mutations in coding regions, to date non-Ig promoter SHMs have been studied only in a handful genes. We designed a novel approach integrating bioinformatics tools with next generation sequencing technology to identify regulatory loci targeted by SHM genome-wide. We observed increased numbers of SHM associated sequence variant hotspots in lymphoma cells as compared to primary normal germinal center B cells. Many of these SHM hotspots map to genes that have not been reported before as mutated, including BACH2, BTG2, CXCR4, CIITA, EBF1, PIM2, and TCL1A, etc., all of which have potential roles in B cell survival, differentiation, and malignant transformation. In addition, using BCL6 and BACH2 as examples, we demonstrated that SHM sites identified in these 5' regulatory regions greatly altered their transcription activities in a reporter assay. Our approach provides a first cost-efficient, genome-wide method to identify regulatory mutations and non-Ig SHM hotspots.

Alternate JournalPLoS ONE
PubMed ID22808135
PubMed Central IDPMC3395700
Grant ListR01 CA104348 / CA / NCI NIH HHS / United States