Novel SF3B1 in-frame deletions result in aberrant RNA splicing in CLL patients.
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ABSTRACT:
SUBMITTER: Agrawal AA
PROVIDER: S-EPMC5728324 | biostudies-literature | 2017 Jun
REPOSITORIES: biostudies-literature
Publications
Novel <i>SF3B1</i> in-frame deletions result in aberrant RNA splicing in CLL patients.
Agrawal Anant A AA Seiler Michael M Brinton Lindsey T LT Mantel Rose R Lapalombella Rosa R Woyach Jennifer A JA Johnson Amy J AJ Zhu Ping P Warmuth Markus M Yu Lihua L Byrd John C JC Smith Peter G PG Blachly James S JS Buonamici Silvia S
Blood advances 20170614 15
We identify and characterize novel <i>SF3B1</i> in-frame deletions in chronic lymphocytic leukemia.These deletions are functionally similar to well-known <i>SF3B1</i> hotspot mutations and are sensitive to splicing modulation. ...[more]
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Project description: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.
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