Haematologica. 2014 Jan;99(1):28-36. doi: 10.3324/haematol.2013.091249. Epub 2013 Aug 30.
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.
TET2、IDH1 和 IDH2 的体细胞突变已在骨髓增生异常综合征中被描述。这些突变对骨髓增生异常综合征的结果及其向继发性急性髓系白血病的进展的影响尚不清楚。在一组 46 对骨髓增生异常综合征/急性髓系白血病样本和 122 例新发骨髓增生异常综合征的非配对病例中，研究了 TET2、IDH1 和 IDH2 的突变状态，以阐明它们在骨髓增生异常综合征向急性髓系白血病演变中的作用。在 168 例新发骨髓增生异常综合征患者中，TET2、IDH1 和 IDH2 突变的频率分别为 18.5%、4.2%和 6.0%。TET2/IDH 突变对生存率没有影响，而 TET2 突变与快速向急性髓系白血病进展显著相关。在 46 对骨髓增生异常综合征/继发性急性髓系白血病样本中，有 17 例存在 TET2/IDH 突变；在急性髓系白血病阶段，没有获得这些突变。在 17 例存在 TET2/IDH 突变的病例中，有 12 例进展为急性髓系白血病伴随着一个新的克隆的演变或一个或多个不同突变的次要预先存在亚克隆的扩张。在 3 例存在 TET2 双等位基因失活的亚克隆随后扩张的情况下，表明 TET2 双等位基因突变在急性髓系白血病进展中起作用。12 例患者获得了其他遗传病变，并且/或者在急性髓系白血病进展过程中显示 FLT3-ITD、N/K-RAS、CEBPA 或 RUNX1 的相对突变等位基因负担增加。我们的研究结果为 TET2/IDH 突变在骨髓增生异常综合征发病机制及其随后向急性髓系白血病进展中的作用提供了新的见解。
