Acquired mutations in TET2 are common in myelodysplastic syndromes

Myelodysplastic syndromes (MDS) represent a heterogeneous group of neoplastic hematopoietic disorders. 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 performed SNP-array-based genomic profiling and genomic sequencing in 102 patients. We identified acquired deletions, missense and nonsense mutations in a new gene, TET2, in 26% of MDS patients. Using allele-specific assays, TET2 mutations were shown to be present in the majority of the myeloid cells (56-100%, 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.