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Altered DNA methylation profiles in SF3B1 mutated CLL patients

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Item Type:Article
Title:Altered DNA methylation profiles in SF3B1 mutated CLL patients
Creators Name:Pacholewska, A. and Grimm, C. and Herling, C.D. and Lienhard, M. and Königs, A. and Timmermann, B. and Altmüller, J. and Mücke, O. and Reinhardt, H.C. and Plass, C. and Herwig, R. and Hallek, M. and Schweiger, M.R.
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 SF3B1(mut) 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.
Keywords:Chronic Lymphocytic Leukemia, CLL, DNA Methylation, SF3B1 Mutation, NOTCH, IKAROS
Source:International Journal of Molecular Sciences
Page Range:9337
Date:1 September 2021
Official Publication:http://doi.org/10.3390/ijms22179337
PubMed:View item in PubMed

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