title: 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.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hsin-An
authors.initials: HA
authors.lastname: Hou
authors.affiliation: Biostatistics Consulting Laboratory, Department of Nursing, National Taipei College of Nursing, Taipei, Taiwan.
authors.forename: Chieh-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yuan-Yeh
authors.initials: YY
authors.lastname: Kuo
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wen-Chien
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Tai-Chang Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Cheng-Hong
authors.initials: CH
authors.lastname: Tsai
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Chin
authors.initials: CC
authors.lastname: Lin
authors.affiliation: Clinical Laboratory Science and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Liang-In
authors.initials: LI
authors.lastname: Lin
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Mei-Hsuan
authors.initials: MH
authors.lastname: Tseng
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Chiang
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming-Chih
authors.initials: MC
authors.lastname: Liu
authors.affiliation: Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Wen
authors.initials: CW
authors.lastname: Liu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Jih-Luh
authors.initials: JL
authors.lastname: Tang
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Tai-Chang Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Li
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shang-Yi
authors.initials: SY
authors.lastname: Huang
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.affiliation: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Szu-Chun
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chien-Yuan
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.|Tai-Chang Stem Cell Therapy Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Ting
authors.initials: CT
authors.lastname: Lin
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Shang-Ju
authors.initials: SJ
authors.lastname: Wu
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Woei
authors.initials: W
authors.lastname: Tsay
authors.affiliation: Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tien
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics*; D000072668:Splicing Factor U2AF / Q000235:genetics*; D055815:Young Adult
chemical_list: C473949:ASXL1 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D000072260:RNA Splicing Factors; C493728:RUNX1 protein, human; D012097:Repressor Proteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D049308:Dioxygenases; C541081:TET2 protein, human
keywords: de novo AML; paired sample; prognosis; splicing factor mutations
references.citation: Leukemia. 2008 May;22(5):915-31
references.pmid: 18288131
references.citation: Blood. 2015 Feb 26;125(9):1367-76
references.pmid: 25550361
references.citation: Blood. 2002 Oct 1;100(7):2387-92
references.pmid: 12239146
references.citation: Int J Cancer. 2013 Jul;133(1):260-5
references.pmid: 23280334
references.citation: J Clin Oncol. 2011 Apr 1;29(10):1364-72
references.pmid: 21343560
references.citation: Blood. 2012 Jan 12;119(2):559-68
references.pmid: 22077061
references.citation: Leukemia. 2008 May;22(5):1075-8
references.pmid: 17972951
references.citation: Am J Hematol. 2014 Aug;89(8):E109-15
references.pmid: 24723457
references.citation: Blood. 2010 Apr 8;115(14):2749-54
references.pmid: 20097881
references.citation: Leukemia. 2012 Dec;26(12):2447-54
references.pmid: 22678168
references.citation: Blood. 2014 May 22;123(21):3327-35
references.pmid: 24668493
references.citation: Blood. 2010 Jun 24;115(25):5222-31
references.pmid: 20368469
references.citation: Blood. 2014 Aug 21;124(8):1304-11
references.pmid: 24923295
references.citation: Nature. 2011 Sep 11;478(7367):64-9
references.pmid: 21909114
references.citation: Cancer Res. 2006 Mar 15;66(6):3310-6
references.pmid: 16540685
references.citation: Cancer Genet Cytogenet. 1995 Oct 1;84(1):60-8
references.pmid: 7497445
references.citation: Blood. 2011 Oct 6;118(14):3803-10
references.pmid: 21828143
references.citation: Blood. 2012 Oct 11;120(15):3106-11
references.pmid: 22932795
references.citation: Leukemia. 2002 Feb;16(2):196-202
references.pmid: 11840285
references.citation: Am J Hematol. 2014 Feb;89(2):181-6
references.pmid: 24127063
references.citation: Am J Hematol. 2013 Nov;88(11):E277-82
references.pmid: 23861105
references.citation: Blood. 2009 Dec 17;114(26):5352-61
references.pmid: 19808697
references.citation: Clin Cancer Res. 2005 Feb 15;11(4):1372-9
references.pmid: 15746035
references.citation: Am J Hematol. 2014 Feb;89(2):137-44
references.pmid: 24115220
references.citation: Leukemia. 2014 Aug;28(8):1586-95
references.pmid: 24487413
references.citation: N Engl J Med. 2013 May 30;368(22):2059-74
references.pmid: 23634996
references.citation: Nat Rev Mol Cell Biol. 2009 Nov;10(11):741-54
references.pmid: 19773805
references.citation: Blood Cancer J. 2014 Jan 17;4:e177
references.pmid: 24442206
references.citation: Blood Cancer J. 2015 Jul 31;5:e331
references.pmid: 26230955
references.citation: Int J Hematol. 2012 Oct;96(4):438-42
references.pmid: 23054646
references.citation: Blood. 2012 Jan 12;119(2):569-72
references.pmid: 22096241
references.citation: N Engl J Med. 2011 Oct 13;365(15):1384-95
references.pmid: 21995386
references.citation: J Clin Oncol. 2003 Dec 15;21(24):4642-9
references.pmid: 14673054
references.citation: Leukemia. 2014 Jan;28(1):50-8
references.pmid: 23929217
references.citation: Blood. 2011 Dec 8;118(24):6239-46
references.pmid: 21998214
references.citation: Blood. 2012 Apr 5;119(14 ):3211-8
references.pmid: 22343920
references.citation: Nature. 2014 Feb 20;506(7488):328-33
references.pmid: 24522528
references.citation: Blood. 2012 Apr 12;119(15):3578-84
references.pmid: 22389253
references.citation: N Engl J Med. 2005 Jan 20;352(3):254-66
references.pmid: 15659725