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

GNAS复合轨迹 RNA剪接 生物 选择性拼接 突变体 生物信息学 组学 遗传学 基因 表型 计算生物学 核糖核酸 信使核糖核酸
作者
Emily C. Wheeler,Shailee Vora,Daniel Mayer,Andriana G. Kotini,Malgorzata Olszewska,Samuel S. Park,Ernesto Guccione,Julie Teruya‐Feldstein,Lewis R. Silverman,Roger K. Sunahara,G Yeo,Eirini P. Papapetrou
出处
期刊:Cancer Discovery [American Association for Cancer Research]
卷期号:12 (3): 836-855 被引量:41
标识
DOI:10.1158/2159-8290.cd-21-0508
摘要

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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