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Mutations in splicing factor SF3B1 promote transformation through MYC stabilization

UID: 10590

Author(s): Yoshimi, Akihide*, Fabbri, Giulia * MSK affiliated

Description
Summary from the GEO: "Although mutations in the RNA splicing factor SF3B1 are frequently observed in multiple human cancers, their functional role in promoting tumorigenesis and therapeutic significance remain poorly understood. Here we characterize the splicing landscape of 79 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations, identifying hundreds of cryptic 3’ splice site (ss) events shared as well as specific to different tumor types. Regulatory network analysis shows that tumors harboring the most common hotspot mutation in SF3B1 (SF3B1K700E) activate the MYC transcriptional program. SF3B1 mutations lead to a dramatic decay of transcripts encoding the key PP2A phosphatase subunit PPP2R5A due to aberrant 3’ss usage, resulting in increased c-MYC serine 62 phosphorylation (allowing MYC to escape ubiquitin-mediated degradation) and in increased BCL2 serine 70 phosphorylation (leading to anti-apoptotic effects). This effect of SF3B1K700E on c-MYC and BCL2 activation through post-translational regulation was conserved across human and mouse cells and could be rescued by restored expression of PPP2R5A. Consonant with this, mutant SF3B1 promoted c-MYC driven tumorigenesis could be restored by the PP2A activating agent FTY-720. This study reveals the functional contribution of mutant SF3B1 to tumorigenesis through regulation of established oncogenic pathways and provides therapeutic strategies for related tumors."

Overall design from the GEO: "16 samples, including 12 mouse and 4 human samples with varying SF3B1 status"
Subject of Study
Homo sapiens
Mus musculus
Subject(s)
Proto-Oncogene Proteins c-myc
RNA Splicing Factors
Access via GEO

TAB Data of expression profiling by high throughput sequencing
Accession #: GSE116391

Access via SRA

RNA Sequence reads for 20 samples.
Accession #: SRP151562

Access via BioProject

Additional information about overall initiative.
Accession #: PRJNA478381

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications
Liu Z, Yoshimi A, Wang J, et al. Mutations in the RNA splicing factor SF3B1 promote tumorigenesis through MYC stabilization. Cancer Discovery. 2020; 10(6):806-821.
Data Type
Genomic
Equipment Used
Illumina HiSeq 2000

High throughput gene sequencing system

Dataset Format(s)
SRA, TAR, TAB
Dataset Size
48.3MB (TAR of TAB), 104.2 Gb (SRA)
Data Catalog Record Updated
2023-12-07