|
| Status |
Public on May 01, 2020 |
| Title |
Mutations in splicing factor SF3B1 promote transformation through MYC stabilization |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
|
| Summary |
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.
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| |
|
| Overall design |
16 samples, including 12 mouse and 4 human samples with varying SF3B1 status
|
| |
|
| Contributor(s) |
Yoshimi A, Fabbri G |
| Citation(s) |
32188705 |
| |
| Submission date |
Jun 28, 2018 |
| Last update date |
Nov 03, 2021 |
| Contact name |
Zhaoqi Liu |
| E-mail(s) |
liuzq@big.ac.cn
|
| Phone |
6466593600
|
| Organization name |
Columbia university
|
| Department |
Systems Biology
|
| Lab |
The Rabadan Lab
|
| Street address |
ICRC Building 8th Floor, Office 803B 1130 St. Nicholas Ave
|
| City |
NewYork |
| State/province |
New York |
| ZIP/Postal code |
10032 |
| Country |
USA |
| |
|
| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
|
| Samples (16)
|
|
| Relations |
| BioProject |
PRJNA478381 |
| SRA |
SRP151562 |
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