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Acquired mutations in TET2 are common in myelodysplastic syndromes


Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders1. Several recurrent chromosomal aberrations have been associated with MDS, but the genes affected have remained largely unknown. To identify relevant genetic lesions involved in the pathogenesis of MDS, we conducted SNP array–based genomic profiling and genomic sequencing in 102 individuals with MDS and identified acquired deletions and missense and nonsense mutations in the TET2 gene in 26% of these individuals. Using allele-specific assays, we detected TET2 mutations in most of the bone marrow cells (median 96%). In addition, the mutations were encountered in various lineages of differentiation including CD34+ progenitor cells, suggesting that TET2 mutations occur early during disease evolution. In healthy tissues, TET2 expression was shown to be elevated in hematopoietic cells with highest expression in granulocytes, in line with a function in myelopoiesis. We conclude that TET2 is the most frequently mutated gene in MDS known so far.

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Figure 1: Copy number changes and uniparental disomy in MDS.
Figure 2: TET2 is recurrently affected in MDS.
Figure 3: Localization of TET2 mutations.
Figure 4: Expression of three TET2 isoforms in various cells and tissues.
Figure 5: Correlation of TET2 mutation status and allelic burden with clinical phenotype.

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We thank G. Merkx, J. van Velzen, R. Woestenenk, S. van Reijmersdal, E. Verwiel and C. van den Elzen for technical assistance and J. Boezeman for help with the statistical analyses. W.A.F. Marijt (Leiden University Medical Center) contributed subject samples. This work was supported by grants from the “Dutch Organization for Scientific Research” (NWO, 92003420), the “Stichting Vanderes” (07-183) and the “Dutch Cancer Society” (KWF). P.V.D.B. is a clinical investigator of FWO Vlaanderen.

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S.M.C.L., R.P.K., M.B., M.G.A., B.A.v.d.R., T.d.W. and J.H.J. designed experiments. S.M.C.L., M.B., R.K., M.G.A. and E.V. isolated subject material. R.P.K., A.G.v.K. and E.J.K. were responsible for the SNP-array hybridizations and data analyses. E.S.-L., M.M., P.v.H., M.G.A., R.K. and M.B. performed sequencing experiments and T-cell cultures. P.V., E.V., G.E.V., A.H., T.d.W. and R.A.P.R. provided subject material and participated in discussions. J.H.J. and S.M.C.L. wrote the paper.

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Correspondence to Joop H Jansen.

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Langemeijer, S., Kuiper, R., Berends, M. et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41, 838–842 (2009).

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