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Updated: Oct 20, 2025
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients
Alicja Pacholewska1,2, Christina Grimm1,2, Carmen D Herling3
1Institute for Translational Epigenetics, Faculty of Medicine, University Hospital Cologne, 50931 Cologne, Germany.
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.
Insights
Mutations in the SF3B1 gene impact chronic lymphocytic leukemia (CLL) patient survival. These SF3B1 mutations lead to specific DNA methylation changes in CLL, affecting cancer-related genes.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Splicing factor gene mutations significantly affect cancer patient survival.
- SF3B1 mutations are common in chronic lymphocytic leukemia (CLL) and associated with poor prognosis.
- The interplay between B cell epigenetics, SF3B1 mutations, and DNA methylation in CLL is not well understood.
Purpose of the Study:
- To investigate the effect of SF3B1 mutations on the epigenome of CLL patients.
- To explore the relationship between B cell epigenetic stages, SF3B1 mutations, and DNA methylation alterations in CLL.
Main Methods:
- Genome-wide DNA methylation profiling of 27 CLL patients (with and without SF3B1 mutations).
- Identification and analysis of differentially methylated regions (DMRs) associated with SF3B1 mutations.
- Correlation of DMRs with B cell developmental epigenetic stages and cancer-related genes.
Main Results:
- Identified 67 genomic regions with decreased methylation in SF3B1-mutated CLL patients, often near telomeres.
- Differentially methylated regions (DMRs) were enriched in gene bodies of key cancer-signaling genes (e.g., NOTCH1, HTRA3, BCL9L).
- SF3B1 mutations occurred in specific B cell epigenetic developmental stages, but DMRs suggested additional mutation-induced epigenetic changes.
Conclusions:
- SF3B1 mutations in CLL are associated with distinct, localized DNA hypomethylation patterns.
- These methylation alterations target critical cancer-related genes, potentially contributing to disease progression.
- SF3B1 mutations induce epigenetic aberrations beyond normal B cell development methylation programming in CLL.
