title: Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations.
abstract: Somatic mutations of TET2, IDH1, and IDH2 have been described in myelodysplastic syndrome. The impact of these mutations on outcome of myelodysplastic syndrome and their progression to secondary acute myeloid leukemia remains unclear. Mutation status of TET2, IDH1 and IDH2 was investigated in a cohort of 46 paired myelodysplastic syndrome/acute myeloid leukemia samples and 122 non-paired cases with de novo myelodysplastic syndrome, to clarify their roles in the evolution of myelodysplastic syndrome to acute myeloid leukemia. Among the 168 de novo myelodysplastic syndrome patients, the frequency of TET2, IDH1, and IDH2 mutations was 18.5%, 4.2% and 6.0%, respectively. TET2/IDH mutations had no impact on survivals, while TET2 mutations were significantly associated with rapid progression to acute myeloid leukemia. Seventeen of the 46 paired myelodysplastic syndrome/secondary acute myeloid leukemia samples harbored TET2/IDH mutations; none acquired these mutations in acute myeloid leukemia phase. Progression to acute myeloid leukemia was accompanied by evolution of a novel clone or expansion of a minor pre-existing subclone of one or more distinct mutations in 12 of the 17 cases with TET2/IDH mutations. A minor subclone in 3 cases with biallelic TET2 inactivation subsequently expanded, indicating biallelic TET2 mutations play a role in acute myeloid leukemia progression. Twelve patients acquired other genetic lesions, and/or showed increased relative mutant allelic burden of FLT3-ITD, N/K-RAS, CEBPA or RUNX1 during acute myeloid leukemia progression. Our findings provide a novel insight into the role of TET2/IDH mutation in the pathogenesis of myelodysplastic syndrome and subsequent progression to acute myeloid leukemia.
authors.affiliation: sly7012@adm.cgmh.org.tw/sogawa-tky@umin.ac.jp.
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Lin
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Nagata
authors.forename: Hsiao-Wen
authors.initials: HW
authors.lastname: Kao
authors.forename: Masashi
authors.initials: M
authors.lastname: Sanada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Okuno
authors.forename: Chein-Fuang
authors.initials: CF
authors.lastname: Huang
authors.forename: Der-Cherng
authors.initials: DC
authors.lastname: Liang
authors.forename: Ming-Chung
authors.initials: MC
authors.lastname: Kuo
authors.forename: Chang-Liang
authors.initials: CL
authors.lastname: Lai
authors.forename: En-Hui
authors.initials: EH
authors.lastname: Lee
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Shih
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Tung-Huei
authors.initials: TH
authors.lastname: Lin
authors.forename: Jin-Hou
authors.initials: JH
authors.lastname: Wu
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Lee-Yung
authors.initials: LY
authors.lastname: Shih
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D018450:Disease Progression; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D059785:Karyotype; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human