Chuanyou Xia, Thale Kristin Olsen, Ali Zirakzadeh, Radwa Almamoun, Louise K Sjöholm, Jan Sjöberg, Hans-Erik Claesson, John Inge Johnsen, Ola Winqvist, Jenny Dahlström, Dawei Xu, Tomas J Ekström, Magnus Björkholm and Klas Strååt
We previously reported hodgkin lymphoma (HL) development in two triplets where all three were homozygotic and had a constitutional deletion in the first intron of the megakaryoblastic leukemia 1 gene (MKL1) (Bjorkholm M et al, Development of hodgkin lymphoma in homozygotic triplets with constitutional deletion in MKL1. Blood. 2013; 121(23):4807). DNA methylation is thought to play an important role in carcinogenesis. Due to the accordant genome in all triplets, the epigenetic pattern especially the methylation status is of great interest. Four types of cells were isolated from peripheral blood samples of triplets: Naïve B-cells, CD34+ cells, switched memory B-cells, and marginal zone like B-cells. Subsequently, DNA methylation was analyzed using the illumina EPIC array with 850.000 CpG site-specific probes. Differences in DNA methylation were found in CD34+ cells, naïve B-cells and marginal zone like B-cells. An overview of the workflow and results is presented in (Fig. 1). In naïve B-cells we found one region on chromosome 19 that differed in DNA methylation, however, one of the HL-affected triplets displayed a hypermethylated region while the other HL-triplet displayed a hypomethylated region as compared to the non-affected triplet. In marginal zone like B-cells, we found 14 genomic regions (two regions had almost complete overlap), spread out on 9 chromosomes, which were all hypermethylated in both HL-affected triplets as opposed to the non-affected triplet. In these regions, genes related to HL and other cancers or hematopoiesis (CYGB; ISM1; KLHL22; MRAS; SNHG16; KDR) were identified. In CD34+ cells we found one region on chromosome 12 where the two HL-affected triplets showed a hypomethylated region as compared to the non-affected triplet. This region was located between gene CCDC65 and FKBP11. These DNAmethylation differences in CD34+ cells and specific B-cell subtypes may contribute to the HL pathogenesis in two of the triplets.
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