Ten-eleven Translocation 2 Expression Research Articles

Low Ten-eleven-translocation 2 (TET2) transcript level is independent of TET2 mutation in patients with myeloid neoplasms.

BackgroundNew sequencing technologies have enabled the identification of mutations in Ten-eleven-translocation 2 (TET2), an enzyme that catalyzes the conversion of 5-methylcytosine into 5-hydroxymethylcytosine (5-hmC) in myeloid neoplasms. We have recently identified reduced TET2 mRNA expression in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which is associated with a poor overall survival in MDS. We herein aimed to investigate TET2 mutations and their impact on TET2 expression in a cohort of patients with myeloid neoplasms, including MDS and AML patients.FindingsTET2 mutations were observed in 8 out of 19 patients (42 %) with myeloid neoplasms. The TET2 expression profile was similar between in wild type and in TET2 mutated patients.ConclusionOur results suggest that TET2 expression is reduced in MDS/AML patients, independently of mutational status.

Decrease of TET2 expression and increase of 5-hmC levels in myeloid sarcomas

BackgroundMyeloid sarcoma is a tumor mass that consists of myeloblasts or immature myeloid cells at an extramedullary site. Pathological diagnosis is very difficult based on morphology if systemic signs of disease are absent. The subtype of myeloid sarcoma is also minimally identifiable in the histological picture. FindingsWe investigated 18 paraffin-embedded myeloid sarcoma samples, and our immunohistochemical data confirmed the relevance of some key markers for the diagnosis and subclassification of myeloid sarcoma. CD34 was found as a marker in 67% of the myeloid sarcoma cases, and CD34 was positive in all immature types of myeloid sarcoma. CD68 was found in 83% of the myeloid sarcoma cases, but CD68 was most identified in the differentiated type of myeloid sarcoma. Myeloperoxidase (MPO) was positive in all myeloid sarcomas. Notably, the reactivity of MPO in the blastic subtype was much lower in myeloid sarcomas. CD117 reactivity was found in 67% of myeloid sarcomas. Ten-eleven translocation 2 (TET2) protein exhibited significant negative reactivity in 88% of the cases, and 5-methylcytosine (5-hmC) was significantly positive in the nucleus in 100% of the cases. ConclusionsOur findings indicated that an immunohistochemical panel that included MPO, CD68 and CD34 could be used for the detection of blastic, differentiated and immature types of myeloid sarcoma. Changes in novel epigenetic regulators, including the loss of TET2 and gain of 5-hmC, as characteristics of myeloid malignancies may be useful novel markers of myeloid sarcoma.

Recurrent TET2 Mutations in Adult T Cell Leukemia (ATL) and Identification of a Single Nucleotide Polymorphism in TET2 Region Predisposing to ATL Development

ATL (Adult T cell leukemia) is a rare and mature T cell malignancy due to HTLV-1 retrovirus infection that bears poor prognosis. Four subtypes are described: two indolent forms (smoldering and chronic) and two aggressive forms (acute and lymphoma) that are mostly resistant to conventional therapies. The clinical story of the disease begins by viral infection mostly during childhood and leads, in around 5% of infected individuals, to transformation of T lymphocyte CD4 with a long latency period. Beside the role of the two viral oncoproteins Tax and HBZ and some others human genes as TP53, p16, TCF8, little is known about other somatic genomic alterations that contribute to lymphomagenesis. Little is also known about genetic risk factors being susceptible to ATL development after HTLV-1 infection. Only few studies have shown that specific HLA haplotypes can predispose to ATL in Japanese population.Deregulation of DNA methylation, such as inactivation of the Ten-ElevenTranslocation 2 (TET2) gene by haplo-insufficiency, has been identified in malignant hematologic diseases. Inactivating mutations of TET2 were first described in myeloid disorders and more recently in peripheral T-cell lymphomas especially those that are harboring T follicular helper features like angio-immunoblastic T cell lymphoma.In order to determine new oncogenic pathways in HTLV-1-associated adult T cell leukemia (ATL), we have investigated the presence of TET2 coding sequence mutations and their clinical relevance in a retrospective cohort of 71 ATL patients. Mono allelic inactivating mutations of the TET2 gene were found in 14 patients (20%). Out of the 60 patients with aggressive forms (acute and lymphoma), 13 (22%) had TET2 mutations versus only one (9%) out of the 11 patients with indolent forms. This last patient had nevertheless a worst outcome. Five patients present a monoallelic somatic mutation. Strikingly, 9 out of the 14 mutated patients showed the same point mutation previously described as a Single Nucleotide polymorphism (SNP), which creates a frameshift resulting in the introduction of a premature stop codon in the TET2 sequence and leads to haplo-insufficiency. In order to functionally characterize the TET2 protein encoded by the Tet2 recurrent variant, the SNP sequence was introduced in a TET2 expression vector. The WT and mutated constructs were transfected in 293T cells. Their expression and activity were analyzed. As expected, the mutation results in the production of a truncated form of TET2, whose DNA hydroxylase activity was dramatically reduced as compared to WT TET2The tet2 SNP frequency is not uniform worldwide and varies by ethnic origins. It is about 5% in the African population and less than 1% in other populations worldwide (1000 genomes database). We then addressed whether this SNP is predisposal for HTLV-1 infection or ATL development by sequencing the SNP region in 143 HTLV-1 carriers mostly originated from French Guyana, matching the African or French Caribbean origins of our ATL cohort. The frequency of this SNP in this control carrier population was 5%, similar to what is observed among African population. A significantly higher frequency was found in the ATL cohort: 13% (p=0,0416, OR=2,820; 95%CI, 1,004 to 7,921).In conclusion, we have shown that somatic TET2 mutations are associated with ATL especially in aggressive forms. Moreover, we have identified and characterized a TET2 SNP, which is associated to TET2 loss of function and that may predispose to ATL development like HLA haplotypes in Japan, while infected with HTLV-1. DisclosuresNo relevant conflicts of interest to declare.

Low Shear Stress Inhibited Endothelial Cell Autophagy Through TET2 Downregulation.

Low shear stress plays a crucial role in the initiation and progression of atherosclerotic lesions. However, the detailed mechanisms of these processes remain unclear. In this study, the effect of low shear stress on endothelial cell autophagy and its potential mechanism were investigated. Results showed autophagy dysfunction and ten-eleven translocation 2 (TET2) protein downregulation during atherosclerotic lesion progression. Autophagic markers BECLIN 1 and LC3II/LC3I under low shear stress (5dyne/cm(2)) obviously decreased compared with those under physiological shear stress (15dyne/cm(2)), whereas autophagic substrate p62 increased. TET2 expression was also downregulated under low shear stress. Endothelial cell autophagy was improved with TET2 overexpression but was impaired by TET2 siRNA treatment. Moreover, TET2 overexpression upregulated the expression of endothelial cell nitric oxide synthase (eNOS) and downregulated the expression of endothelin-1 (ET-1). TET2siRNA further attenuated eNOS expression and stimulated ET-1 expression. Overall, the results showed that low shear stress downregulated endothelial cell autophagy by impaired TET2 expression, which might contribute to theatherogenic process.

Ten-eleven-translocation 2 (TET2) is downregulated in myelodysplastic syndromes.

TET2, a member of the ten-eleven-translocation (TET) family genes that modify DNA by converting 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), is located in chromosome 4q24 and is frequently mutated in myeloid malignancies. The impact of TET2 mutation on survival outcomes is still controversial; however, functional studies have proved that it is a loss-of-function mutation that impairs myeloid cell differentiation and contributes to the phenotype of myeloid neoplasia. We, herein, aimed to investigate TET2 expression in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). A significantly decreased TET2 expression was observed in bone marrow cells from AML (n = 53) and patients with MDS (n = 64), compared to normal donors (n = 22). In MDS, TET2 expression was significantly reduced in RAEB-1/RAEB-2 compared to other WHO 2008 classifications, and a lower TET2 expression was observed at the time of MDS disease progression in four of five patients. In multivariate analysis, low TET2 expression (P = 0.03), male gender (P = 0.02), and WHO 2008 classification (P < 0.0001) were independent predictors of poorer overall survival. These results suggest that defective TET2 expression plays a role in the MDS pathophysiology and predicts survival outcomes in this disease.

An Extensive Network of TET2-Targeting MicroRNAs Regulates Malignant Hematopoiesis

The Ten-Eleven-Translocation 2 (TET2) gene, which oxidates 5-methylcytosine in DNA to 5-hydroxylmethylcytosine (5hmC), is a key tumor suppressor frequently mutated in hematopoietic malignancies. However, the molecular regulation of TET2 expression is poorly understood. We show that TET2 is under extensive microRNA (miRNA) regulation, and such TET2 targeting is an important pathogenic mechanism in hematopoietic malignancies. Using a high-throughput 3' UTR activity screen, we identify >30 miRNAs that inhibit TET2 expression and cellular 5hmC. Forced expression of TET2-targeting miRNAs invivo disrupts normal hematopoiesis, leading to hematopoietic expansion and/or myeloid differentiation bias, whereas coexpression of TET2 corrects these phenotypes. Importantly, several TET2-targeting miRNAs, including miR-125b, miR-29b, miR-29c, miR-101, and miR-7, are preferentially overexpressed in TET2-wild-type acute myeloid leukemia. Our results demonstrate the extensive roles of miRNAs in functionally regulating TET2 and cellular 5hmC and reveal miRNAs with previously unrecognized oncogenic potential. Our work suggests that TET2-targeting miRNAs might be exploited in cancer diagnosis.