Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms.
Abstract
Mutations in splicing factors (SF) are the predominant class of mutations in myelodysplastic syndrome (MDS), but convergent downstream disease drivers remain elusive. To identify common direct targets of missplicing by mutant U2AF1 and SRSF2, we performed RNA sequencing and enhanced version of the cross-linking and immunoprecipitation assay in human hematopoietic stem/progenitor cells derived from isogenic induced pluripotent stem cell (iPSC) models. Integrative analyses of alternative splicing and differential binding converged on a long isoform of GNAS (GNAS-L), promoted by both mutant factors. MDS population genetics, functional and biochemical analyses support that GNAS-L is a driver of MDS and encodes a hyperactive long form of the stimulatory G protein alpha subunit, Gαs-L, that activates ERK/MAPK signaling. SF-mutant MDS cells have activated ERK signaling and consequently are sensitive to MEK inhibitors. Our findings highlight an unexpected and unifying mechanism by which SRSF2 and U2AF1 mutations drive oncogenesis with potential therapeutic implications for MDS and other SF-mutant neoplasms. SF mutations are disease-defining in MDS, but their critical effectors remain unknown. We discover the first direct target of convergent missplicing by mutant U2AF1 and SRSF2, a long GNAS isoform, which activates G protein and ERK/MAPK signaling, thereby driving MDS and rendering mutant cells sensitive to MEK inhibition. This article is highlighted in the In This Issue feature, p. 587.
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Linked Datasets (1)
Integrative RNA-omics discovers GNAS alternative splicing as a phenotypic driver of splicing factor mutant neoplasms
Homo sapiens58 data files
| File | Type | Size |
|---|---|---|
| SRR13416241.lite | RNA-Seq | 3.4 GB |
| SRSF2_hpc.P95L-1_INPUT_R1_001.fastq.gz | OTHER | 658.9 MB |
| SRSF2_hpc.P95L-1_INPUT_R1_001.fastq.gz | OTHER | 658.9 MB |
| SRSF2_hpc.P95L-1_IP_R1_001.fastq.gz | OTHER | 945.7 MB |
| SRSF2_hpc.P95L-1_IP_R1_001.fastq.gz | OTHER | 945.7 MB |
| SRSF2_hpc.P95L-2_INPUT_R1_001.fastq.gz | OTHER | 853.6 MB |
| SRSF2_hpc.P95L-2_INPUT_R1_001.fastq.gz | OTHER | 853.6 MB |
| SRSF2_hpc.P95L-2_IP_R1_001.fastq.gz | OTHER | 932.7 MB |
| SRSF2_hpc.P95L-2_IP_R1_001.fastq.gz | OTHER | 932.7 MB |
| SRSF2_hpc.WT-1_INPUT_R1_001.fastq.gz | OTHER | 912.2 MB |
| SRSF2_hpc.WT-1_INPUT_R1_001.fastq.gz | OTHER | 912.2 MB |
| SRSF2_hpc.WT-1_IP_R1_001.fastq.gz | OTHER | 741.6 MB |
| SRSF2_hpc.WT-1_IP_R1_001.fastq.gz | OTHER | 741.6 MB |
| SRSF2_hpc.WT-2_INPUT_R1_001.fastq.gz | OTHER | 760.0 MB |
| SRSF2_hpc.WT-2_INPUT_R1_001.fastq.gz | OTHER | 760.0 MB |
| SRSF2_hpc.WT-2_IP_R1_001.fastq.gz | OTHER | 744.4 MB |
| SRSF2_hpc.WT-2_IP_R1_001.fastq.gz | OTHER | 744.4 MB |
| SRSF2-P95L-1-rnaseq_R1.fastq.gz | RNA-Seq | 3.8 GB |
| SRSF2-P95L-1-rnaseq_R1.fastq.gz | RNA-Seq | 3.8 GB |
| SRSF2-P95L-2-rnaseq_R1.fastq.gz | RNA-Seq | 3.0 GB |
| SRSF2-P95L-2-rnaseq_R1.fastq.gz | RNA-Seq | 3.0 GB |
| SRSF2-P95L-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.9 GB |
| SRSF2-P95L-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.9 GB |
| SRSF2-P95L-4-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| SRSF2-P95L-4-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| U2AF1_hpc.S34F-1_INPUT_R1_001.fastq.gz | OTHER | 1.3 GB |
| U2AF1_hpc.S34F-1_INPUT_R1_001.fastq.gz | OTHER | 1.3 GB |
| U2AF1_hpc.S34F-1_IP_R1_001.fastq.gz | OTHER | 2.0 GB |
| U2AF1_hpc.S34F-1_IP_R1_001.fastq.gz | OTHER | 2.0 GB |
| U2AF1_hpc.S34F-2_INPUT_R1_001.fastq.gz | OTHER | 1.4 GB |
| U2AF1_hpc.S34F-2_INPUT_R1_001.fastq.gz | OTHER | 1.4 GB |
| U2AF1_hpc.S34F-2_IP_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.S34F-2_IP_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.WT-1_INPUT_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.WT-1_INPUT_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.WT-1_IP_R1_001.fastq.gz | OTHER | 1.5 GB |
| U2AF1_hpc.WT-1_IP_R1_001.fastq.gz | OTHER | 1.5 GB |
| U2AF1_hpc.WT-2_INPUT_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.WT-2_INPUT_R1_001.fastq.gz | OTHER | 1.2 GB |
| U2AF1_hpc.WT-2_IP_R1_001.fastq.gz | OTHER | 1.4 GB |
| U2AF1_hpc.WT-2_IP_R1_001.fastq.gz | OTHER | 1.4 GB |
| U2AF1-S34F-1-rnaseq_R1.fastq.gz | RNA-Seq | 4.5 GB |
| U2AF1-S34F-1-rnaseq_R1.fastq.gz | RNA-Seq | 4.5 GB |
| U2AF1-S34F-2-rnaseq_R1.fastq.gz | RNA-Seq | 3.7 GB |
| U2AF1-S34F-2-rnaseq_R1.fastq.gz | RNA-Seq | 3.7 GB |
| U2AF1-S34F-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| U2AF1-S34F-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| WT-1-rnaseq_R1.fastq.gz | RNA-Seq | 3.6 GB |
| WT-1-rnaseq_R1.fastq.gz | RNA-Seq | 3.6 GB |
| WT-2-rnaseq_R1.fastq.gz | RNA-Seq | 3.4 GB |
| WT-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.7 GB |
| WT-3-rnaseq_R1.fastq.gz | RNA-Seq | 3.7 GB |
| WT-4-rnaseq_R1.fastq.gz | RNA-Seq | 4.1 GB |
| WT-4-rnaseq_R1.fastq.gz | RNA-Seq | 4.1 GB |
| WT-5-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| WT-5-rnaseq_R1.fastq.gz | RNA-Seq | 3.5 GB |
| WT-6-rnaseq_R1.fastq.gz | RNA-Seq | 4.0 GB |
| WT-6-rnaseq_R2.fastq.gz | RNA-Seq | 4.0 GB |
Potentially Related Datasets (2)
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome