Splicing factor mutations predict poor prognosis in patients with de novo acute myeloid leukemia
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Hsin-An Hou1, Chieh-Yu Liu2, Yuan-Yeh Kuo3, Wen-Chien Chou1,4, Cheng-Hong Tsai1,5, Chien-Chin Lin1,4, Liang-In Lin6, Mei-Hsuan Tseng1, Ying-Chieh Chiang1, Ming-Chih Liu7, Chia-Wen Liu7, Jih-Luh Tang1, Ming Yao1, Chi-Cheng Li1,5, Shang-Yi Huang1, Bor-Sheng Ko1, Szu-Chun Hsu4, Chien-Yuan Chen1, Chien-Ting Lin1,5, Shang-Ju Wu1, Woei Tsay1 and Hwei-Fang Tien1
1 Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
2 Biostatistics Consulting Laboratory, Department of Nursing, National Taipei College of Nursing, Taipei, Taiwan
3 Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
4 Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan
5 Tai-Chang Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan
6 Clinical Laboratory Science and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
7 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
Hwei-Fang Tien, email:
Keywords: de novo AML, splicing factor mutations, prognosis, paired sample
Received: December 25, 2015 Accepted: January 16, 2016 Published: January 24, 2016
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.
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