title: Impact of TET2, SRSF2, ASXL1 and SETBP1 mutations on survival of patients with chronic myelomonocytic leukemia.
abstract: BACKGROUND
  Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm classified in the myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) category. Molecular abnormalities are reported in about 90 % of patients with CMML. ASXL1 and SETBP1 mutations, but not TET2 or SFRS2 mutations are reported to be associated with prognosis.
  
  
  METHODS
  We studied frequency of TET2, SRSF2, ASXL1 and SETBP1 mutations in 145 patients with CMML using Sanger sequencing, and determined the prognostic factors for OS. We also identified the predictive value of ASXL1 mutations (frameshift and nonsense mutations) through comparing the Mayo Prognostic Model with the Mayo Molecular Model.
  
  
  RESULTS
  Forty-seven (32 %) had a mutation in TET2, 42 (29 %), a mutation in SRSF2, 65 (45 %), a mutation (nonsense and frame-shift) in ASXL1 and 26 (18 %), a mutation in SETBP1. Significant variables in multivariable analysis of survival included ASXL1 (HR = 1.99 [1.20-3.28]; P = 0.007), hemoglobin <100 g/L (HR = 2.42 [1.40-4.19]; P = 0.002) and blood immature myeloid cells (IMCs) (HR = 2.08 [1.25-3.46]; P = 0.005). When our patients were analyzed using the Mayo Prognostic Model median OS were not reached, 26 months and 15 months (P = 0.014). An analysis using the Mayo Molecular Model identified 4 cohorts with median OS of not reached, 70 months, 26 months and 11 months (P < 0.001). Data fitting using our patients suggest the Molecular Mayo Model has significantly higher survival predictive power compared with Mayo Prognostic Model (P < 0.001, -2 log-likelihood ratios of 538.070 and 552.260).
  
  
  CONCLUSIONS
  There were high frequencies of mutations in TET2, SRSF2, ASXL1 and SETBP1 in patients with CMML. With the addition of ASXL1 frameshift and nonsense mutations, the Mayo Molecular Model fitted better than Mayo Prognostic Model of our patients.
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Hematology, The First Affiliated Hospital, ZheJiang University College of Medicine, Zhejiang, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Tong
authors.affiliation: Department of Hematology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Du
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Hematology Research Center, Division of Experimental Medicine, Department of Medicine, Imperial College London, London, UK.
authors.forename: Robert Peter
authors.initials: RP
authors.lastname: Gale
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Jinqin
authors.initials: J
authors.lastname: Liu
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Xu
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Divisions of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Hematology, The First Affiliated Hospital, ZheJiang University College of Medicine, Zhejiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jin
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Fang
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Zhang
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Pan
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Naibo
authors.initials: N
authors.lastname: Hu
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Qu
authors.affiliation: MDS and MPN Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020 China.|State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020 China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Xiao
keywords: Chronic myelomonocytic leukemia; Mutation; Prognostic model