Acquired mutations in TET2 are common in myelodysplastic syndromes

Abstract

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 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.

Mutations of JAK2 and TET2, but not CBL are detectable in a high portion of patients with refractory anemia with ring sideroblasts and thrombocytosis

“…Bortezomib is a proteasome inhibitor that is effective in the treatment of plasma cell dyscrasias. 7 We utilized bortezomib to treat 2 patients with recurrent AL after initial ASCT. Both patients provided written informed consent according to the Helsinki Convention for their initial treatment, for ASCT, for bortezomib treatment of their relapsed disease, and for anonymous data collection.…”

B-cell tumor development in Tet2-deficient mice

“…5 The TET proteins are a-ketoglutarate (a-KG)-dependent dioxygenases able to oxidize 5-methylated cytosine (mC) into hydroxymethylated C (hmC), which represent a step toward active or passive DNA demethylation, or both. The TET2 gene is mutated in 15% of all types of human myeloid neoplasms, [7][8][9] 2% to 10% of B-cell lymphomas, 10,11 and 10% of T-cell lymphomas, particularly of the angioimmunoblastic subtype. 8 However, no major member of the DNA methylation control pathway was recurrently found mutated in CLL and malignant B-cell differentiation.…”

TET2 mutations in childhood leukemia

“…In addition, they may provide novel clues for the development of targeted therapies. TET2 mutations are found in 8-19% of adult AML, 1,5 and the expression of TET2 is high in granulocytes as compared with other hematopoietic and non-hematopoietic cells, where it is increased during myeloid differentiation. 1 Also normal B-cells show high TET2 expression, 1 but TET2 mutations in adult ALL have not been reported.…”

“…Mutations and deletions were detected in myelodysplastic syndromes, acute myeloid leukemias (AML) and other myeloid malignancies. [1][2][3][4][5] So far, however, the presence of TET2 mutations has not been reported in childhood leukemia.…”