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Mutations in the U2 small nuclear RNA auxiliary factor 1 ( U2AF1 ) gene are the common feature of a major subset in myelodysplastic syndromes (MDS). However, the genetic landscape and molecular pathogenesis of oncogenic  U2AF1   S34F   mutation in MDS are not totally understood. We performed comprehensive analysis for prognostic significance of  U2AF1  mutations in acute myeloid leukemia (AML) cohort based on The Cancer Genome Atlas (TCGA) database. Functional analysis of  U2AF1   S34F   mutation was performed in vitro. Differentially expressed genes (DEGs) and significantly enriched pathways were identified by RNA sequencing. The forkhead box protein O3a (FOXO3a) was investigated to mediate the function of  U2AF1   S34F   mutation in cell models using lentivirus. Chromatin immunoprecipitation, immunoblotting analyses, and immunofluorescence assays were also conducted.  U2AF1  mutations were associated with poor prognosis in MDS and AML samples, which significantly inhibited cell proliferation and induced cellular apoptosis in cell models. Our data identified that  U2AF1 -mutant cell lines undergo FOXO3a-dependent apoptosis and NLRP3 inflammasome activation, which induces pyroptotic cell death. Particularly, an increase in the level of FOXO3a promoted the progression of MDS in association with restored autophagy program leading to NLRP3 inflammasome activation in response to  U2AF1   S34F   mutation. Based on the result that  U2AF1   S34F   mutation promoted the transcriptional activity of  Bim  through upregulating FOXO3a with transactivation of cell cycle regulators  p21   Cip1   and  p27   Kip1  , FOXO3a, a potentially cancer-associated transcription factor, was identified as the key molecule on which these pathways converge. Overall, our studies provide new insights that  U2AF1   S34F   mutation functions the crucial roles in mediating MDS disease progression via FOXO3a activation, and demonstrate novel targets of  U2AF1  mutations to the pathogenesis of MDS.

U2AF1 mutation promotes tumorigenicity through facilitating autophagy flux mediated by FOXO3a activation in myelodysplastic syndromes