Haematologica (Jan 2014)

Clonal leukemic evolution in myelodysplastic syndromes with TET2 and IDH1/2 mutations

  • Tung-Liang Lin,
  • Yasunobu Nagata,
  • Hsiao-Wen Kao,
  • Masashi Sanada,
  • Yusuke Okuno,
  • Chein-Fuang Huang,
  • Der-Cherng Liang,
  • Ming-Chung Kuo,
  • Chang-Liang Lai,
  • En-Hui Lee,
  • Yu-Shu Shih,
  • Hiroko Tanaka,
  • Yuichi Shiraishi,
  • Kenichi Chiba,
  • Tung-Huei Lin,
  • Jin-Hou Wu,
  • Satoru Miyano,
  • Seishi Ogawa,
  • Lee-Yung Shih

DOI
https://doi.org/10.3324/haematol.2013.091249
Journal volume & issue
Vol. 99, no. 1

Abstract

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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.