Pacholewska, Alicja ORCID: 0000-0002-4888-4883, Grimm, Christina ORCID: 0000-0002-4676-8870, Herling, Carmen D., Lienhard, Matthias ORCID: 0000-0002-2549-3142, Koenigs, Anja, Timmermann, Bernd, Altmueller, Janine, Muecke, Oliver, Reinhardt, Hans Christian, Plass, Christoph, Herwig, Ralf, Hallek, Michael and Schweiger, Michal R. (2021). Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients. Int. J. Mol. Sci., 22 (17). BASEL: MDPI. ISSN 1422-0067

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pacholewska, AlicjaUNSPECIFIEDorcid.org/0000-0002-4888-4883UNSPECIFIED
Grimm, ChristinaUNSPECIFIEDorcid.org/0000-0002-4676-8870UNSPECIFIED
Herling, Carmen D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lienhard, MatthiasUNSPECIFIEDorcid.org/0000-0002-2549-3142UNSPECIFIED
Koenigs, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timmermann, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muecke, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herwig, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-591857
DOI: 10.3390/ijms22179337
Journal or Publication Title: Int. J. Mol. Sci.
Volume: 22
Number: 17
Date: 2021
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1422-0067
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CHRONIC LYMPHOCYTIC-LEUKEMIA; GENE LISTS; TRANSCRIPTION; IKAROS; MUTATIONS; SEQUENCE; PROGRESSION; MECHANISM; DATABASE; CANCERMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59185

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