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. 2016 Feb 23;7(8):9084-101.
doi: 10.18632/oncotarget.7000.

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

Hsin-An Hou  1 , Chieh-Yu Liu  2 , Yuan-Yeh Kuo  3 , Wen-Chien Chou  1   4 , Cheng-Hong Tsai  1   5 , Chien-Chin Lin  1   4 , Liang-In Lin  6 , Mei-Hsuan Tseng  1 , Ying-Chieh Chiang  1 , Ming-Chih Liu  7 , Chia-Wen Liu  7 , Jih-Luh Tang  1 , Ming Yao  1 , Chi-Cheng Li  1   5 , Shang-Yi Huang  1 , Bor-Sheng Ko  1 , Szu-Chun Hsu  4 , Chien-Yuan Chen  1 , Chien-Ting Lin  1   5 , Shang-Ju Wu  1 , Woei Tsay  1 , Hwei-Fang Tien  1
Affiliations

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

Hsin-An Hou et al. Oncotarget. .

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.

Keywords: de novo AML; paired sample; prognosis; splicing factor mutations.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. The Circos plots depicted the relative frequency and pairwise co-occurrence of genetic alterations
The length of the arc corresponded to the frequency of the first gene mutation, and the width of the ribbon corresponded to the proportion of the second gene mutation.
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 2
Figure 2. Kaplan-Meier survival curves for overall survival and disease-free survival stratified by the status of SF mutations in total 363 AML patients (A and B), 229 patients with intermediate-risk cytogenetics (C and D) and 161 patients with normal karyotype (E and F) who received standard intensive chemotherapy
Figure 3
Figure 3. Kaplan-Meier survival curves for overall survival (A) and disease-free survival (B) in AML patients based on scoring system (P < 0.001 for both OS and DFS)
AML patients were grouped according to scoring system based on SF mutation and 10 other prognostic markers (CEBPAdouble-mutation, NPM1/FLT3-ITD, IDH2, TP53, WT1, RUNX1 and DNMT3A mutations, cytogenetics, age and WBC counts at diagnosis). A score of -3 was assigned for NPM1+/FLT3-ITD− and -2 for CEBPAdouble-mutation and IDH2 mutation whereas a score of +3 for TP53 mutation and +2 for other factors associated with an adverse outcome (SF, DNMT3A, WT1 and RUNX1 mutations, older age, higher WBC counts at diagnosis and unfavorable cytogenetics). The algebraic summation of these scores of each patient was the final score. This score system divided the AML patients into five groups with different clinical outcomes (P < 0.001 for both OS and DFS). The 12 patients without chromosome data were not included in the analysis.
Figure 3
Figure 3. Kaplan-Meier survival curves for overall survival (A) and disease-free survival (B) in AML patients based on scoring system (P < 0.001 for both OS and DFS)
AML patients were grouped according to scoring system based on SF mutation and 10 other prognostic markers (CEBPAdouble-mutation, NPM1/FLT3-ITD, IDH2, TP53, WT1, RUNX1 and DNMT3A mutations, cytogenetics, age and WBC counts at diagnosis). A score of -3 was assigned for NPM1+/FLT3-ITD− and -2 for CEBPAdouble-mutation and IDH2 mutation whereas a score of +3 for TP53 mutation and +2 for other factors associated with an adverse outcome (SF, DNMT3A, WT1 and RUNX1 mutations, older age, higher WBC counts at diagnosis and unfavorable cytogenetics). The algebraic summation of these scores of each patient was the final score. This score system divided the AML patients into five groups with different clinical outcomes (P < 0.001 for both OS and DFS). The 12 patients without chromosome data were not included in the analysis.
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