54790

TET2

KIAA1546|MDS;tet methylcytosine dioxygenase 2;TET2;tet methylcytosine dioxygenase 2

methylcytosine dioxygenase TET2|probable methylcytosine dioxygenase TET2|tet oncogene family member 2

4q24

protein-coding

TET2 (TET oncogene family member 2) is a candidate tumor suppressor gene located at chromosome 4q24, and was recently reported to be mutated in approximately 14% of patients with JAK2V617F-positive myeloproliferative neoplasms. We used high-throughput DNA sequence analysis to screen for TET2 mutations in bone marrow-derived DNA from 48 patients with systemic mastocytosis (SM), including 42 who met the 2008 WHO (World Health Organization) diagnostic criteria for SM and 6 with FIP1L1-PDGFRA. Twelve (29%) SM, but no FIP1L1-PDGFRA patients, had TET2 mutations. A total of 17 mutations (13 frameshift, 2 nonsense and 2 missense) were documented in 2 (15%) of 13 indolent SM patients, 2 (40%) of 5 aggressive SM, and 8 (35%) of 23 SM associated with a clonal non-mast cell-lineage hematopoietic disease (P=0.52). KITD816V was detected by PCR sequencing in 50 or 20% of patients with or without TET2 mutation (P=0.05), respectively. Multivariable analysis showed a significant association between the presence of TET2 mutation and monocytosis (P=0.0003) or female sex (P=0.05). The association with monocytosis was also observed in non-indolent SM (n=29), in which the presence of mutant TET2 did not affect survival (P=0.98). We conclude that TET2 mutations are frequent in SM, segregate with KITD816V and influence phenotype without necessarily altering prognosis.

Somatic mutations in TET2 occur in patients with myeloproliferative neoplasms and other hematologic malignancies. It has been suggested that TET2 is a tumor suppressor gene and mutations in TET2 precede the acquisition of JAK2-V617F. To examine the order of events, we performed colony assays and genotyped TET2 and JAK2 in individual colonies. In 4 of 8 myeloproliferative neoplasm patients, we found that some colonies with mutated TET2 carried wild-type JAK2, whereas others were JAK2-V617F positive, indicating that TET2 occurred before JAK2-V617F. One of these patients carried a germline TET2 mutation. However, in 2 other patients, we obtained data compatible with the opposite order of events, with JAK2 exon 12 mutation preceding TET2 mutation in one case. Finally, in 2 of 8 patients, the TET2 and JAK2-V617F mutations defined 2 separate clones. The lack of a strict temporal order of occurrence makes it unlikely that mutations in TET2 represent a predisposing event for acquiring mutations in JAK2.

Despite recent progress in molecular research in myeloid malignancies, in subsets of patients with myelodysplastic syndrome (MDS) so far no underlying mutation was identified. In the myeloproliferative neoplasms (MPNs), the JAK2V617F alone cannot explain the phenotypic heterogeneity. In acute myeloid leukemia (AML), clinical variability exists within distinct subgroups. Thus, the search for novel molecular markers continues. Recently, mutations of the tet oncogene family member 2 (TET2) and Casitas B-cell lymphoma (CBL) genes became the focus of interest. With diverse genetic methods, TET2 on chromosome 4q24 was identified as candidate tumor suppressor gene. Sequencing studies revealed heterogeneous mutations in 10-25% of patients with acute myeloid leukemia (AML), MDS, and MPNs, while the frequency might be higher in chronic myelomonocytic leukemia (CMML). The prognostic impact is being explored. The CBL gene is involved in the degradation of tyrosine kinases. In rare cases of human AML (<2%), CBL mutants were identified, with a higher frequency in core binding factor leukemias. Presence of these mutations was suggested to be involved in aberrant FLT3 expression. In the MPNs, a 2-8% frequency of CBL mutations was reported. These novel mutations deepened insights in the mechanisms of leukemogenesis, might contribute to the identification of new therapeutic targets, and improve diagnostics in the myeloid malignancies.

The TET family of proteins has been described a few years ago. Only recently, their roles in DNA modification, through the oxidation of methyl-cytosine, and in normal and malignant development, through the description of TET2 as a tumor suppressor have been documented. The conjunction of these findings has prompted large efforts to understand the biology of these novel entities. Here, we summarize the recent results implicating TET2 in hematological malignancies suggesting that further studies are required to fully understand the role of DNA methylation alterations during transformation.