Abstract
Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery and the epigenome are closely interconnected, we investigated whether these alterations may affect the epigenomes of CLL patients. While an overall hypomethylation during CLL carcinogenesis has been observed, the interplay between the epigenetic stage of the originating B cells and SF3B1 mutations, and the subsequent effect of the mutations on methylation alterations in CLL, have not been investigated. We profiled the genome-wide DNA methylation patterns of 27 CLL patients with and without SF3B1 mutations and identified local decreases in methylation levels in SF3B1mut CLL patients at 67 genomic regions, mostly in proximity to telomeric regions. These differentially methylated regions (DMRs) were enriched in gene bodies of cancer-related signaling genes, e.g., NOTCH1, HTRA3, and BCL9L. In our study, SF3B1 mutations exclusively emerged in two out of three epigenetic stages of the originating B cells. However, not all the DMRs could be associated with the methylation programming of B cells during development, suggesting that mutations in SF3B1 cause additional epigenetic aberrations during carcinogenesis.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and mainly affects elderly people [1]
Principal component analysis with the 1,000 most variable regions within CG islands (CGIs) revealed that samples clustered according to the immunoglobulin heavy chain variable region (IGHV) mutational status, and some separation could be observed based on the SF3B1 mutational status, no clear clusters grouped by the SF3B1 genotype were visible (Figure 1A)
We validated 16 of the significantly differentially methylated regions (DMRs) with the EpiTYPER (Tables S3 and S4) and observed a significant correlation (R = 0.71, p-value < 2.2 × 10−16 ) between the methylation levels of the regions estimated with Methylated DNA immunoprecipitation (MeDIP)-seq/QSEA and EpiTYPER (Figures 1B,C and S1)
Summary
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and mainly affects elderly people [1]. The CLL phenotype is quite specific and homogenous, the clinical outcome is extremely heterogeneous [1]. The clinical outcome is partly associated with the mutational status of the immunoglobulin heavy chain variable region (IGHV) as patients with a high level of somatic mutations in IGHV (M-CLL) have a better prognosis than patients with no or a low level of somatic mutations in this region (U-CLL) [1,2,3]. Shorter progression-free survival is conferred by mutations in the splicing factor 3b subunit 1 (SF3B1), ATM serine/threonine kinase (ATM), ribosomal protein 15 (RPS15), and Notch receptor 1 (NOTCH1) [4,5,6,7,8,9,10]
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