Splicing factor mutations predict poor prognosis in patients with de novo acute myeloid leukemia.

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.

• Authors: Hsin-An Hou, Chieh-Yu Liu, Yuan-Yeh Kuo, Wen-Chien Chou, Cheng-Hong Tsai, Chien-Chin Lin, Liang-In Lin, Mei-Hsuan Tseng, Ying-Chieh Chiang, Ming-Chih Liu, Chia-Wen Liu, Jih-Luh Tang, Ming Yao, Chi-Cheng Li, Shang-Yi Huang, Bor-Sheng Ko, Szu-Chun Hsu, Chien-Yuan Chen, Chien-Ting Lin, Shang-Ju Wu, Woei Tsay, Hwei-Fang Tien
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 8 Pg. 9084-101 (Feb 23 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26812887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ASXL1 protein, human
• Core Binding Factor Alpha 2 Subunit
• DNA-Binding Proteins
• Phosphoproteins
• Proto-Oncogene Proteins
• RNA Splicing Factors
• RUNX1 protein, human
• Repressor Proteins
• SF3B1 protein, human
• Splicing Factor U2AF
• U2AF1 protein, human
• SRSF2 protein, human
• Serine-Arginine Splicing Factors
• IDH2 protein, human
• Isocitrate Dehydrogenase
• Dioxygenases
• TET2 protein, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Base Sequence
• Core Binding Factor Alpha 2 Subunit (genetics)
• DNA-Binding Proteins (genetics)
• Dioxygenases
• Disease-Free Survival
• Female
• Humans
• Isocitrate Dehydrogenase (genetics)
• Leukemia, Myeloid, Acute (genetics)
• Male
• Middle Aged
• Mutation (genetics)
• Phosphoproteins (genetics)
• Proto-Oncogene Proteins (genetics)
• RNA Splicing (genetics)
• RNA Splicing Factors (genetics)
• Repressor Proteins (genetics)
• Sequence Analysis, DNA
• Serine-Arginine Splicing Factors (genetics)
• Splicing Factor U2AF (genetics)
• Young Adult