Abstract
Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but the prognostic relevance of these genes mutations in acute myeloid leukemia (AML) remains unclear. In this study, we investigated mutations of three SF genes, SF3B1, U2AF1 and SRSF2, by Sanger sequencing in 500 patients with de novo AML and analysed their clinical relevance. SF mutations were identified in 10.8% of total cohort and 13.2% of those with intermediate-risk cytogenetics. SF mutations were closely associated with RUNX1, ASXL1, IDH2 and TET2 mutations. SF-mutated AML patients had a significantly lower complete remission rate and shorter disease-free survival (DFS) and overall survival (OS) than those without the mutation. Multivariate analysis demonstrated that SFmutation was an independent poor prognostic factor for DFS and OS. A scoring system incorporating SF mutation and ten other prognostic factors was proved very useful to risk-stratify AML patients. Sequential study of paired samples showed that SF mutations were stable during AML evolution. In conclusion, SF mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. These mutations may be potential targets for novel treatment and biomarkers for disease monitoring in AML.
Highlights
RNA splicing is a crucial post-transcription process that regulates gene expression and increases genomic diversity.[1]
We found that splicing factor (SF) mutation was associated with distinct clinic-biological features and was a poor prognostic factor in acute myeloid leukemia (AML) patients, independent of age, white blood cell (WBC) counts, karyotype and other genetic markers
Similar to the data in myelodysplastic syndrome (MDS), the majority of mutations occurred in hotspot areas: K666N and K700E in SF3B1, S34 and Q157 in U2AF1 and P95 in SRSF2
Summary
RNA splicing is a crucial post-transcription process that regulates gene expression and increases genomic diversity.[1] Recently, somatic mutations involving core components of the RNA splicing machinery were detected in myelodysplastic syndrome (MDS).[2, 3] Mutations of the splicing factor (SF) genes occur most frequently in SRSF2, U2AF1, and SF3B1, and ZRSR2, U2AF2, SF1, SF3A1, PRPF40B, PRPF8 and LUC7L2,[2] with a strong genotype and phenotype association.[4,5,6] Some of these mutations showed prognostic relevance in MDS, discrepancies exist among different studies.[7]. Acute myeloid leukemia (AML) and MDS share some similar mutations in the pathogenesis, differences exist. There has been no report in literature concerning the stability of SF mutations in AML
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