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

Abstract

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 U2AF1S34F 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 U2AF1S34F 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 U2AF1S34F 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 U2AF1S34F mutation. Based on the result that U2AF1S34F mutation promoted the transcriptional activity of Bim through upregulating FOXO3a with transactivation of cell cycle regulators p21Cip1 and p27Kip1, 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 U2AF1S34F 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.

The Biological and Clinical Consequences of RNA Splicing Factor U2AF1 Mutation in Myeloid Malignancies

“…There are four studies reporting that the presence of U2AF1 mutations has no significant impact on the overall survival (OS) or leukemia-free survival in MDS patients [ 26 , 28 , 33 , 43 ]. However, U2AF1 mutations/variants show a significant correlation with worse OS and progression-free survival compared to U2AF1 unmutated cases in multiple MDS patient cohorts [ 23 , 27 , 29 , 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 51 , 52 ]. U2AF1 mutations also predict poor prognosis in the young population and the low-risk subgroup of MDS patients [ 27 ].…”

Differential prognostic impact of cytopenic phenotype in prefibrotic vs overt primary myelofibrosis

“…We showed that cytopenic features, that are more common in overt than pre-PMF, are associated with distinct high-risk clinical and molecular features predominantly in pre-PMF. Of note, U2AF1 mutations emerged as a distinct abnormality of CP in both PMF subtypes, suggesting that they might contribute to ineffective hematopoiesis and reinforcing their adverse prognostic role [ 13 , 14 ]. A CP was associated with inferior OS in both PMF subtypes, and with a higher risk of LT in pre-PMF.…”

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

“…The prognostic impact of U2AF1 mutations and the exact mechanism of U2AF1S34F mutation confers a clonal growth advantage in MDS remain unclear [283,295]. FOXO3a activation is likely involved by increasing oxidative stress, which subsequently alters multiple processes, including apoptosis, autophagy, and immune-inflammatory responses [296].…”