ArticleCancer discovery2022
Integrative RNA-omics Discovers GNAS Alternative Splicing as a Phenotypic Driver of Splicing Factor-Mutant Neoplasms.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- PANoptosis in the pathogenesis of myelodysplastic syndromes.Molecular oncology · 2026Review
- U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.Nature genetics · 2026Article
- U2af1Leukemia · 2026Article
- RNA Regulatory Networks: Key Hubs in the Panorama of Cancer and Emerging Therapeutic Targets.MedComm · 2026Review
- Sequence-dependent splicing dysregulation drives therapy resistance in pediatric AML.Cell reports. Medicine · 2026Article
- Mapping isoforms and regulatory mechanisms from spatial transcriptomics data with SPLISOSM.Nature biotechnology · 2026Article
- Myelodysplastic syndrome progress to acute myeloid leukemia: new insights and updates.Frontiers in immunology · 2026Review
- Modeling myeloid cell development in health and disease using induced pluripotent stem cells.Frontiers in immunology · 2026Review
- SF3B1-mutant models of RNA mis-splicing uncover UBA1 as a therapeutic target in myelodysplastic neoplasms.Leukemia · 2025Article
- U2AF1 mutations rescue deleterious exon skipping induced by KRAS mutations.bioRxiv : the preprint server for biology · 2025Article
- Article
- A clinico-genomic prognostic model for primary myelodysplastic neoplasm in Asia.Blood cancer journal · 2025Article
- Article
- Alternative splicing in stem cells and development: research progress and emerging technologies.Cell regeneration (London, England) · 2025Review
- Understanding Human Oncogene Function and Cooperativity in Myeloid Malignancy Using iPSCs.Experimental hematology · 2025Review
- Decoding cancer etiology with cellular reprogramming.Current opinion in genetics & development · 2025Review
- Aberrant pre-mRNA processing in cancer.The Journal of experimental medicine · 2024Review
- Super-resolution ultrasound and microvasculomics: a consensus statement.European radiology · 2024Review
- Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated GMolecular pharmacology · 2024Review
- Molecular impact of mutations in RNA splicing factors in cancer.Molecular cell · 2024Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
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. SIGNIFICANCE: 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.