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Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms.

Emily C Wheeler, Shailee Vora, Daniel Mayer, Andriana G Kotini, Malgorzata Olszewska, Samuel S Park, Ernesto Guccione, Julie Teruya-Feldstein, Lewis Silverman, Roger K Sunahara, Gene W Yeo, Eirini P Papapetrou

Cancer discovery · 2022 · Vol. 12 (3) · pp. 836-855

PubMed ↗ DOI ↗ PMC full text ↗

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.

Linked datasets 1

GSE164666 GSE · via ncbi_elink
GEO ↗

Integrative RNA-omics discovers GNAS alternative splicing as a phenotypic driver of splicing factor mutant neoplasms

Homo sapiens

60 data files
FileTypeSize
SRR13416240_GSM5016591 RNA-Seq 3.6 GB
SRR13416241_GSM5016592 RNA-Seq 3.4 GB
SRR13416241.lite RNA-Seq 3.4 GB
SRR13416242_GSM5016593 RNA-Seq 3.7 GB
SRR13416243_GSM5016594 RNA-Seq 4.1 GB
SRR13416244_GSM5016595 RNA-Seq 3.5 GB
SRR13416245_GSM5016596 RNA-Seq 4.0 GB
SRR13416246_GSM5016597 RNA-Seq 4.5 GB
SRR13416247_GSM5016598 RNA-Seq 3.7 GB
SRR13416248_GSM5016599 RNA-Seq 3.5 GB
SRR13416249_GSM5016600 RNA-Seq 3.8 GB
SRR13416250_GSM5016601 RNA-Seq 3.0 GB
SRR13416251_GSM5016602 RNA-Seq 3.9 GB
SRR13416252_GSM5016603 RNA-Seq 3.5 GB
SRR13416253_GSM5016575 OTHER 1.2 GB
SRR13416254_GSM5016576 OTHER 1.5 GB
SRR13416255_GSM5016577 OTHER 1.2 GB
SRR13416256_GSM5016578 OTHER 1.4 GB
SRR13416257_GSM5016579 OTHER 1.3 GB
SRR13416258_GSM5016580 OTHER 2.0 GB
SRR13416259_GSM5016581 OTHER 1.4 GB
SRR13416260_GSM5016582 OTHER 1.2 GB
SRR13416261_GSM5016583 OTHER 912.0 MB
SRR13416262_GSM5016584 OTHER 741.0 MB
SRR13416263_GSM5016585 OTHER 760.0 MB
SRR13416264_GSM5016586 OTHER 744.0 MB
SRR13416265_GSM5016587 OTHER 658.0 MB
SRR13416266_GSM5016588 OTHER 945.0 MB
SRR13416267_GSM5016589 OTHER 853.0 MB
SRR13416268_GSM5016590 OTHER 932.0 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-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.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-2_INPUT_R1_001.fastq.gz OTHER 760.0 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-2-rnaseq_R1.fastq.gz RNA-Seq 3.0 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
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-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.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-2_INPUT_R1_001.fastq.gz OTHER 1.2 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-2-rnaseq_R1.fastq.gz RNA-Seq 3.7 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-2-rnaseq_R1.fastq.gz RNA-Seq 3.4 GB
WT-3-rnaseq_R1.fastq.gz RNA-Seq 3.7 GB
WT-4-rnaseq_R1.fastq.gz RNA-Seq 4.1 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 3

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.

Accession Source Title
GSE63816 GSE · GEO GEO ↗ Aberrant splicing of U12-type introns is the hallmark of ZRSR2 mutant myelodysplastic syndrome
GSE114922 GSE · GEO GEO ↗ RNA sequencing of bone marrow CD34+ hematopoietic stem and progenitor cells from patients with myelodysplastic syndrome and healthy controls
GSE164666 GSE · GEO GEO ↗ Integrative RNA-omics discovers GNAS alternative splicing as a phenotypic driver of splicing factor mutant neoplasms

Analysis pipelines 3

Pipeline Assay Steps Dataset
GSE114922 RNA-seq Data Processing geo_data_processing RNA-seq 7 GSE114922
GSE164666 eCLIP Data Processing geo_data_processing eCLIP 4 GSE164666
GSE63816 RNA-seq Data Processing geo_data_processing RNA-seq 6 GSE63816
Funding 10 grants
Grant Funder
U24 HG009889 NHGRI NIH HHS (United States)
R01 HG004659 NHGRI NIH HHS (United States)
U41 HG009889 NHGRI NIH HHS (United States)
T32 GM008666 NIGMS NIH HHS (United States)
R01 HL137223 NHLBI NIH HHS (United States)
F31 CA228295 NCI NIH HHS (United States)
R01 HL121570 NHLBI NIH HHS (United States)
R01 CA225231 NCI NIH HHS (United States)
R01 HL137219 NHLBI NIH HHS (United States)
R01 GM083118 NIGMS NIH HHS (United States)