GID complex regulates the differentiation of neural stem cells by destabilizing TET2 / 医学前沿

Brain development requires a delicate balance between self-renewal and differentiation in neural stem cells (NSC), which rely on the precise regulation of gene expression. Ten-eleven translocation 2 (TET2) modulates gene expression by the hydroxymethylation of 5-methylcytosine in DNA as an important epigenetic factor and participates in the neuronal differentiation. Yet, the regulation of TET2 in the process of neuronal differentiation remains unknown. Here, the protein level of TET2 was reduced by the ubiquitin-proteasome pathway during NSC differentiation, in contrast to mRNA level. We identified that TET2 physically interacts with the core subunits of the glucose-induced degradation-deficient (GID) ubiquitin ligase complex, an evolutionarily conserved ubiquitin ligase complex and is ubiquitinated by itself. The protein levels of GID complex subunits increased reciprocally with TET2 level upon NSC differentiation. The silencing of the core subunits of the GID complex, including WDR26 and ARMC8, attenuated the ubiquitination and degradation of TET2, increased the global 5-hydroxymethylcytosine levels, and promoted the differentiation of the NSC. TET2 level increased in the brain of the Wdr26+/- mice. Our results illustrated that the GID complex negatively regulates TET2 protein stability, further modulates NSC differentiation, and represents a novel regulatory mechanism involved in brain development.

Prognostic factors of autologous hematopoietic stem cell transplantation in intermediate-risk acute myeloid leukemia patients with minimal residual disease negativity / 中华内科杂志

To explore prognostic factors in intermediate-risk acute myeloid leukemia (AML) patients with minimal residual disease (MRD) negativity (MRD<0.1%,MRD-)receiving autologous hematopoietic stem cell transplantation (auto-HSCT).A total of 59 intermediate-risk AML patients with MRD-were treated with auto-HSCT from January 2015 to September 2021 at Affiliated People′s Hospital of Ningbo University. The clinical data and laboratory results were collected retrospectively. Efficacy, clinical outcome and prognostic factors were analyzed. Univariate analysis was conducted by using log-rank test, the multivariate analysis by Cox proportional risk model.Among 59 patients, there were 27 males and 32 females with median age of 55 (31-69) years old.The median follow-up was 761(317-1 861)days. The 2-year overall survival (OS) rate and event-free survival (EFS) rate were 76.1%±11.4% and 73.4%±11.6% respectively.The univariate analysis showed that age older than 50 years, TET2 gene mutation (TET2 +), achieving MRD negativity over 30 days (MRD 30+) were unfavorable factors of OS ( χ2=6.20, 33.20, 7.18; P=0.013,<0.001, 0.007). TET 2+, WT1 gene mutation (WT1 +), CD34 +cells<2×10 6/kg, MRD 30+were negative factors of EFS ( χ2=17.29, 4.47, 3.94, 9.393; P<0.001, 0.035, 0.047, 0.002).Multivariate analysis showed that MRD 30+, TET2 + were independent prognostic factors of OS and EFS (OS: HR=9.251, 25.839, P=0.036, 0.001;EFS: HR=5.851, 9.199, P=0.043, 0.002). Intermediate-risk AML patients with MRD 30+or TET2 + have very poor prognosis after auto-HSCT. Alternative regimens should be investigated.

Analysis of Gene Mutation Characteristics and Prognosis of Elderly Patients with Acute Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To investigate the characteristics of gene mutation in elderly patients with acute myeloid leukemia (AML) and its effect on prognosis.@*METHODS@#The clinical and laboratorial characteristics of 54 AML patients (≥60 years old) in Department of Hematology, Tangdu Hospital were analyzed retrospectively during April 2016 to October 2019. Thirty-four AML/myelodysplastic syndrome/myeloproliferative neoplasm related mutant genes were detected by second-generation sequencing technology, and their clinical characteristics, treatment effect, and influence on prognosis were analyzed.@*RESULTS@#All the patients received DAC+CAG induction treatment, after 1-2 couses of treatment, 36 cases (66.7%) achieved complete response, with a total effective rate of 75.9%, and the median survival time was 17 months. The most frequent mutant genes were TET2 (33.3%), CEBPA (31.5%), DNMT3A (18.5%), ASXL1 (16.7%), NRAS (14.8%), RUNX1 (14.8%), FLT3-ITD (12.9%), TP53 (12.9%), NPM1 (12.9%), and IDH2 (12.9%). Among 7 patients with TP53 mutation, 6 cases obtained complete response after 1-2 courses of induction treatment, but there was no statistically significant difference in the effect on prognosis. Patients with FLT3-ITD and NRAS mutations had shorter overall survival time compared with who had no mutation (P=0.47, P=0.48). Multivariate analysis showed that FLT3-ITD and NRAS mutations were poor prognostic factors.@*CONCLUSION@#The incidence of TET2 gene mutation is high in elderly AML patients. AML patients with TET2 and TP53 mutations may benefit from Decitabine-based chemotherapy. However, patients with FLT3-ITD and NRAS mutations have a short survival time, and may have a poor prognosis.

Analysis of clinical significance and prognostic impact of TET2 single nucleotide polymorphism I1762V in patients with acute myeloid leukemia / 中华血液学杂志

Objective: This study aimed to investigate the clinical and prognostic significance of TET2 single nucleotide polymorphism I1762V in patients with acute myeloid leukemia (AML) . Methods: The high-throughput sequencing method was used to sequence 58 hematological tumor-related genes in bone marrow samples from 413 patients with AML. TET2 I1762V and other somatic mutations were annotated and compared with patients' clinical information and prognosis. Results: I1762V was found in 154 patients with AML, which was significantly different from the general population in NyuWa Chinese Population Variant Database (χ(2)=72.4, P<0.001) . I1762V was not related to sex, age, and karyotype of patients with AML (P>0.05) . Patients with I1762V had a significantly higher proportion of NPM1 and KIT gene mutations than others (P<0.001) . NPM1 and KIT mutations were mutually exclusive. The survival analysis results revealed that the overall survival (OS) and progression-free survival (PFS) of patients with AML with I1762V were significantly greater than those of wild-type patients (HR=0.57, P=0.030; HR=0.55, P=0.020) , whereas the OS and PFS in patients with AML with DNMT3A mutation (with or without I1762V mutation) were lower than those of wild-type patients (HR=1.79, P=0.030; HR=1.74, P=0.040) . Conclusion: TET2 SNP I1762V has been linked to AML. I1762V is a prognostic factor of patients with AML, which can be used to guide the treatment and evaluate the prognosis of AML.

The function and regulation of TET2 in innate immunity and inflammation

TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe

Clinical characteristics of acute myeloid leukemia patients with TET2 gene mutation and effects of TET2 mutation on therapeutic efficacy and prognosis / 白血病·淋巴瘤

Objective:To investigate clinical features of adult patients with acute myeloid leukemia (AML) with TET2 gene mutation and effects of TET2 mutation on therapeutic efficacy and prognosis.Methods:A total of 123 newly diagnosed adult AML patients (except for acute promyelocytic leukemia) admitted to Jining No.1 People's Hospital from March 2017 to April 2021 were selected. Mutations of 24 AML-related genes including TET2 mutation were detected by using second-generation sequencing technology. Patients were divided into two groups according to the presence of TET2 mutation: TET2 mutation group and TET2 wild type group. The differences in clinicopathological characteristics, short-term efficacy and survival of both groups were compared.Results:Among 123 patients, TET2 mutation was detected in 28 cases (22.8%). Compared with TET2 wild type group, the patients were older [(59±15) years vs.(49±16) years, t = 2.984, P = 0.003], French-American-British (FAB) Corporative Group M 4 and M 5 subtypes were more common [75.0% (21/28) vs. 51.6% (49/95), χ2 = 4.838, P = 0.028], and the positive rate of CD34 in AML patients was lower in TET2 mutation group [46.4% (13/28) vs.72.6% (69/95), χ2 = 6.685, P = 0.010]. Moreover, TET2 mutation was more likely to be accompanied with ZRSR2 mutation [10.7% (3/28) vs. 1.1% (1/95), P = 0.037] and NPM1 mutation [35.7% (10/28) vs.17.9% (17/95), χ2 = 4.008, P = 0.045], but less likely to be accompanied with IDH1/2 mutation [0 vs.17.9% (17/95), P = 0.012]. However, there were no statistically significant differences in gender, peripheral blood leukocyte count at initial diagnosis, hemoglobin level, platelet count, bone marrow blasts ratio, cytogenetics and the European LeukemiaNet (ELN) risk stratification between the two groups (all P>0.05). In addition, there were no significant differences in the overall response rate (ORR) of 1 cycle chemotherapy [75.0% (12/16) vs. 66.7% (42/63), χ2 = 0.410, P = 0.522] and demethylation therapy [66.7% (4/6) vs. 44.4% (8/18), P = 0.640]. The difference in overall survival (OS) of both groups was not statistically significant [median OS time: 23 months (95% CI 5-41 months) vs. 35 months (95% CI 18-52 months, P = 0.498]. Conclusions:In AML patients, TET2 mutation is associated with advanced age, M 4 and M 5 subtypes, and low expression of CD34 on AML blasts. TET2 mutation is commonly accompanied by ZRSR2 and NPM1 mutation, but not IDH1 or IDH2 mutation. TET2 mutation may have no significant effects on therapeutic efficacy and survival in the whole cohort of AML patients without risk stratification.

Study on synergistic inhibitory effect of ruxolitinib and decitabine on growth of HEL cells with TET2 knockdown / 中国药理学通报

Aim To explore the cytotoxic and synergistic effects of decitabine and ruxolitinib on HEL cells with TET2 knockdown. Methods Stable TET2 knockdown by shRNA was established in HEL cell line. The change of cell proliferation was measured by CCK-8 assay. The median lethal dose (IC50) and colony formation assay were used to evaluate the cytotoxic effects of decitabine and ruxolitinib, the synergistic effects of which was further analyzed by Chou-Talalay method. Results The inhibition of TET2 increased the proliferative capacity of HEL cells. HEL cell lines became resistant to decitabine following shRNA-media- ted TET2 inactivation. Colony formation assay showed that the drug sensitivity of decitabine and ruxolitinib both decreased in TET2 knockdown HEL cells. The synergistic inhibitory effects of ruxolitinib and decitabine on TET2 knockdown HEL cells were observed. Conclusion The combination of ruxolitinib and decitabine may be an effective therapeutic strategy for accelerated or blast phase MPN patients with JAK2V6m and TET2 mutations.

miR-660-5p promotes breast cancer progression through down-regulating TET2 and activating PI3K/AKT/mTOR signaling

Breast cancer (BC) is a commonly diagnosed cancer in females. MicroRNA-660-5p (miR-660-5p) has been reported to be involved in the occurrence and development of BC. However, the regulatory network of miR-660-5p in BC has not been fully addressed. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the enrichment of miR-660-5p and tet-eleven translocation 2 (TET2) in BC tissues and cells. Cell counting kit-8 (CCK8), flow cytometry, and transwell migration and invasion assays were used to measure cell proliferation, apoptosis, migration, and invasion. The target relationship between miR-660-5p and TET2 was confirmed by dual luciferase reporter assay. Protein expression was measured by western blot. The expression of miR-660-5p was elevated in BC, and high expression of miR-660-5p was closely related to lymph node metastasis, advanced TNM stage, and vascular invasion of BC tumors. miR-660-5p silencing inhibited cell proliferation and metastasis, but induced apoptosis of BC cells. TET2 was identified as a direct target of miR-660-5p, and the interference of TET2 partly reversed the suppressive effects of miR-660-5p silencing on the malignant potential of BC cells. miR-660-5p promoted BC progression partly through modulating TET2 and PI3K/AKT/mTOR signaling. miR-660-5p/TET2 axis might be a promising target for BC treatment.

Effects of TET2-targeting miR-27b on oxidized low-density lipoprotein-induced inflammatory responses and apoptosis in endothelial cells / 中华微生物学和免疫学杂志

Objective@#To investigate the effects of miR-27b targeting ten-eleven translocation methylcytosine dioxygenase 2 (TET2) on oxidized low-density lipoprotein (ox-LDL) induced inflammatory responses and apoptosis in endothelial cells.@*Methods@#Double luciferase reporter gene analysis verified the targeting effect of miR-27b on TET2. Human umbilical vein endothelial cells (HUVECs) were induced by ox-LDL in vitro. Eight groups were set up including control group, ox-LDL group, ox-LDL+ anti-miR-con group, ox-LDL+ anti-miR-27b group, ox-LDL+ pcDNA group, ox-LDL+ pcDNA-TET2 group, anti-miR-27b+ si-con group and anti-miR-27b+ si-TET2 group. qRT-PCR was used to detect the expression of miR-27b and TET2 at mRNA level. Cell viability was detected by MTT assay. Cell apoptosis rate was detected by flow cytometry. Western blot was used to detect the expression of TET2, Cyclin D1 and caspase-3 at protein level.@*Results@#TET2 was the target gene of miR-27b. TET2 expression could be negatively regulated by miR-27b. ox-LDL increased the expression of miR-27b and reduced the expression of TET2 in HUVECs. The secretion of inflammatory factors and apoptosis rates of HUVECs in the control, ox-LDL+ anti-miR-27b, ox-LDL+ pcDNA-TET2 and anti-miR-27b+ si-con groups were significantly lower than those in the ox-LDL, ox-LDL+ anti-miR-con, ox-LDL+ pcDNA and anti-miR-27b+ si-TET2 groups, respectively (P<0.05).@*Conclusions@#miR-27b promoted ox-LDL-induced inflammatory responses and apoptosis in endothelial cells through down-regulating the expression of TET2.

Correlation between single nucleotide polymorphism of TET2 gene and susceptibility and prognosis of sepsis / 中华急诊医学杂志

Objective To investigate the association of SNPs in TET2 gene with the susceptibility and prognosis of sepsis.Methods Ninety-nine patients diagnosed with sepsis and 107 controls were enrolled in the study.The septic patients were further divided into survivors (56 cases) and non-survivors (43 cases) according to the outcome of 28-day hospitalization.Patients without sepsis after major surgery were enrolled as the controls.The genotypes of the five loci (rs6839705,rs7670522,rs7679673,rs7698522 and rs10010325) with high minor allele frequency in the TET2 were screened according to the existing research reports and the SNP database of the NCBI website.The five loci were detected by TaqMan probe based allelic discrimination assays using real-time polymerase chain reaction (PCR).The data were calculated for genetic association study through x2 test and Fisher's exact probability method.Results There was no significant difference in genotype frequencies of the five tested SNPs in TET2 gene between septic patients and controls or between survivors and non-survivors in septic patients (P ＞ 0.05).Furthermore,the allelic frequencies of the five SNPs between septic patients and controls or between survivors and non-survivors in septic patients also had no significant difference (P ＞ 0.05).Conclusions This study showed that the five SNPs in TET2 gene (rs6839705,rs7670522,rs7679673,rs7698522,and rs10010325) were not associated with the susceptibility and prognosis of sepsis,which needs to be further confirmed by large-sample studies.

Correlation between single nucleotide polymorphism of TET2 gene and susceptibility and prognosis of sepsis / 中华急诊医学杂志

Objective@#To investigate the association of SNPs in TET2 gene with the susceptibility and prognosis of sepsis.@*Methods@#Ninety-nine patients diagnosed with sepsis and 107 controls were enrolled in the study. The septic patients were further divided into survivors (56 cases) and non-survivors (43 cases) according to the outcome of 28-day hospitalization. Patients without sepsis after major surgery were enrolled as the controls. The genotypes of the five loci (rs6839705, rs7670522, rs7679673, rs7698522 and rs10010325) with high minor allele frequency in the TET2 were screened according to the existing research reports and the SNP database of the NCBI website. The five loci were detected by TaqMan probe based allelic discrimination assays using real-time polymerase chain reaction (PCR). The data were calculated for genetic association study through χ2 test and Fisher’s exact probability method.@*Results@#There was no significant difference in genotype frequencies of the five tested SNPs in TET2 gene between septic patients and controls or between survivors and non-survivors in septic patients (P > 0.05). Furthermore, the allelic frequencies of the five SNPs between septic patients and controls or between survivors and non-survivors in septic patients also had no significant difference (P > 0.05).@*Conclusions@#This study showed that the five SNPs in TET2 gene (rs6839705, rs7670522, rs7679673, rs7698522, and rs10010325) were not associated with the susceptibility and prognosis of sepsis, which needs to be further confirmed by large-sample studies.

Expressions of BAP1 and TET2 proteins in bone marrow of patients with chronic myelomonocytic leukemia and their significances / 白血病·淋巴瘤

Objective To investigate the expressions of BAP1 and TET2 proteins in bone marrow of patients with chronic myelomonocytic leukemia (CMML) and their relationship with the prognosis of CMML. Methods The bone marrow paraffin specimens of 41 cases from 41 adult CMML patients diagnosed by Shanghai Sino-US Joint Leukemia Coordination Group from September 2003 to May 2007 were collected. The immunohistochemistry was used to detect the expressions of BAP1 and TET2 proteins in 41 CMML patients. The expressions of TET2 and BAP1 proteins were also detected by the same method in 40 adult patients with acute myelomonocytic leukemia (AMML) and 20 patients with iron deficiency anemia (IDA) diagnosed at the same time as the comparison. The clinical data of 41 CMML patients were analyzed by using retrospective cohort study. The count data were compared by using chi-square test. The correlation between expressions of BAP1 and TET2 proteins was analyzed by using Pearson correlation analysis. Kaplan-Meier method was used to calculate the survival time, and Log-rank test was used for single factor analysis. Results In 41 CMML patients, the positive expression rate of BAP1 was 31.7％ (13/41), including 28.6％ (8/28) in CMML-1 patients and 38.5％ (5/13) in CMML-2 patients; the positive expression rate of TET2 was 41.5％ (17/41), including 39.3％ (11/28) in CMML-1 patients and 46.2％ (6/13) in CMML-2 patients. In 40 AMML patients, the positive expression rate of BAP1 was 32.5％ (13/40), and the positive expression rate of TET2 was 35.0％ (14/40). In 20 IDA patients, the positive expression rate of BAP1 was 5.0％ (1/20), and TET2 had no positive expression. There was no significant difference in the expressions of BAP1 and TET2 proteins between CMML-1 and CMML-2 patients (χ 2 = 0.40, P = 0.53; χ 2 = 0.17, P = 0.68). There was no significant difference in the expressions of BAP1 and TET2 proteins between CMML and AMML patients (χ 2 = 0.01, P = 0.94; χ 2 = 0.36, P = 0.64). There were significant differences in the positive expression rate of BAP1 and TET2 proteins between hematological neoplastic disease (CMML+AMML) and hematological non-neoplastic disease (IDA) (χ 2 = 6.01, P < 0.05; χ 2 = 11.04, P < 0.01). Pearson correlation analysis showed that there was no correlation between expressions of BAP1 and TET2 proteins (r = 0.35, P = 0.27). Univariate analysis showed that anemia (Hb < 60 g/L), mature monocyte count ≥ 2.0×109/L, neutrophil count (1.5×109/L), abnormal karyotype were associated with poor prognosis for CMML. Protein expressions of BAP1 and TET2 were not related with the prognosis of CMML (χ 2 = 0.28, P = 0.600; χ 2 = 0.53, P = 0.460). Conclusion Both BAP1 and TET2 proteins have high positive expression rates in CMML patients, but the expressions of them are not related to the prognosis.

The progress of pathogenesis and treatment in angioimmunoblastic T-cell lymphoma / 中国肿瘤临床

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphomas. It is a fol-licular T-helper-derived neoplasm, and characterized by the presence of some genetic alterations, such as mutations in TET2, DN-MT3A, IDH2, and RHOA. Anthracycline-containing regimens represent the most widely adopted first-line option; however, new biolog-ic agents should be designed and incorporated to improve treatment response. The elucidation of the specific roles of these genetic al-terations in AITL will facilitate the development of molecularly targeted therapies to treat this disease.

The effect of DNA hydroxymethylase Tet2 on γ globin activation in the treatment of β-thalassemia / 中华内科杂志

Objective To study the function of ten-eleven translocation 2 (Tet2) in γglobin gene expression in patients with β-thalassemia.Methods Gamma globin expression was induced by 5-azacytidine and Tet2 gene expression was knocked down by short hairpin RNA (shRNA) in a human immortalized myelogenous leukemia K562 cell line.The global 5-hydroxymethylcytosine (5hmC) level was measured by an ELISA kit.5hmC level of γglobin gene was quantified by sulfite sequencing.The mRNA level of Tet2,γglobin,and related transcription factors Nfe4 and Klfl were quantified by real-time PCR.Results Tet2 knockdown resulted in a decreased global 5hmC level from 0.14％ to 0.03％ as of the control group in K562 cells.The expression of γ globin was enhanced after 5-azacytidine treatment in vitro.However,γglobin mRNA level in Tet2 knockdown cells was only 55％ as that in control group.The CG sites on γ globin gene were unmethylated.As Tet2 was down-regulated,the expression levels of Nfe4 and Klf1 decreased by about 80％ and increased to 3.5 folds,respectively.Conclusions Tet2 appears to maintain 5hmC level and facilitates γ globin gene activation.Moreover,Tet2 more likely regulates γglobin expression via affecting transcription factors rather than the gene itself.Thus,Tet2 could be a potential therapeutic target for β thalassemias.

Tet2 Regulates Osteoclast Differentiation by Interacting with Runx1 and Maintaining Genomic 5-Hydroxymethylcytosine (5hmC) / 基因组蛋白质组与生物信息学报·英文版

As a dioxygenase, Ten-Eleven Translocation 2 (TET2) catalyzes subsequent steps of 5-methylcytosine (5mC) oxidation. TET2 plays a critical role in the self-renewal, proliferation, and differentiation of hematopoietic stem cells, but its impact on mature hematopoietic cells is not well-characterized. Here we show that Tet2 plays an essential role in osteoclastogenesis. Deletion of Tet2 impairs the differentiation of osteoclast precursor cells (macrophages) and their maturation into bone-resorbing osteoclasts in vitro. Furthermore, Tet2 mice exhibit mild osteopetrosis, accompanied by decreased number of osteoclasts in vivo. Tet2 loss in macrophages results in the altered expression of a set of genes implicated in osteoclast differentiation, such as Cebpa, Mafb, and Nfkbiz. Tet2 deletion also leads to a genome-wide alteration in the level of 5-hydroxymethylcytosine (5hmC) and altered expression of a specific subset of macrophage genes associated with osteoclast differentiation. Furthermore, Tet2 interacts with Runx1 and negatively modulates its transcriptional activity. Our studies demonstrate a novel molecular mechanism controlling osteoclast differentiation and function by Tet2, that is, through interactions with Runx1 and the maintenance of genomic 5hmC. Targeting Tet2 and its pathway could be a potential therapeutic strategy for the prevention and treatment of abnormal bone mass caused by the deregulation of osteoclast activities.

Resistance to daunorubicin in acute myeloid leukemia is associated with mutations in the TET2 gene / 安徽医科大学学报

Objective To investigate the effect of leukemia-related genes on drug resistance in patients with acute myeloid leukemia (AML). Methods 74 patients with newly diagnosed AML were selected and 54 leukemia-associated genes of all patients were sequenced by second-generation gene sequencing. The gene with the highest mutation rate was further analyzed in association with resistance to several common chemotherapy medicines in in vitro drug sensitivity assays. In addition, in vitro drug resistance data were compared with the clinical data of patients. Results The TET2 gene was the most frequent mutation among 74 patients with newly diagnosed AML, with 11 positive patients. Among these 11 TET2 positive patients, 9 (81. 82％ ) were resistant to daunorubicin, while only 4 (6. 35％ ) out of 63 TET2 negative patients were resistant to daunorubicin. Besides, there was no significant difference between in vitro resistance rate to daunorubicin and the clinical data of patients. Conclusion TET2 gene mutation is associated with resistance to daunorubicin in AML patients, which may become an important indicator of the therapeutic efficacy of DA regimen.

The challenge for allogeneic hematopoietic stem cell transplantation in acute leukemia/ myelodyplastic syndrom with TP53, TET2 or DNMT3A gene mutations / 天津医药

@#Recently, much gene mutations have been detected in patients with acute leukemia or myelodysplastic syndrome (MDS) using next-generation sequencing (NSG) technology. Some of them are proved to be important prognostic markers. It has been showed that TP53, TET2 or DNMT3A gene mutations are associated with poor prognosis in acute leukemia or MDS patients. The prognosis of these patients is poor with short remission and survival. Allogeneic hematopoietic stem cell transplantation is the only way to cure these patients. However, the outcomes after transplantation are inferior to those in patients without these mutations. The hypomethylating agents or immune targeting therapy might improve their prognosis when combined with the present strategies. Here, the impact of TP53, TET2 and DNMT3A gene mutations on the prognosis after chemotherapy or transplantation is reviewed.

TET2 is upregulated during erythroid differentiation of CD34+ cells from healthy donors and myelodysplastic syndrome patients

Background: Tet methylcytosine dioxygenase 2 (TET2) is frequently mutated and/or downregulated in myeloid neoplasm, including myelodysplastic syndromes. Despite the extensive studies, the specific contribution of TET2 in disease phenotype of myeloid neoplasms is not fully elucidated. Recent findings have grown attention on the role of TET2 in normal and malignant erythropoiesis. Methods: In the present study, we investigated TET2 mRNA levels by quantitative PCR during erythropoietin-induced erythroid differentiation CD34+ cells from healthy donor and myelodysplastic syndrome patients. Statistical analyses were performed using the ANOVA and Bonferroni post hoc test and a p-value <0.05 was considered statically significant. Results: TET2 expression is upregulated during erythroid differentiation of CD34+ cells from healthy donor and myelodysplastic syndrome patients. Conclusions: Our findings corroborate that TET2 is involved in the erythrocyte differentiation (AU)

MicroRNA-10a promotes granulosa cells tumor development / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of microRNA-10a on the development of granulosa cells tumor (GCT). METHODS FISH was used to detect the miR-10a expression in tissues from GCT patients. Several functional assays were performed to investigate the effect of miR-10a on proliferation,migration, invasion, spheroid formation and repressed anticancer drug-induced apoptosis of GCT in vitro.CRISPR- Cas9 system mediated miR- 10a knockout in cancer GC and two mice GCT models wereconstructed to show the knockdown effect of miR-10a on cancer GC both in vitro and in vivo. RNA-seq,Western blot, luciferase reporter assay and FISH were used to identify potential direct functional targets and related pathways of miR-10a in cancer GC. RESULTS Strong miR-10a signal was detected in tissues from malignant GCT patients. And amplification of miR- 10a negatively correlated with overall survival rate of ovarian cancer patients. In addition, ectopic expression of miR- 10a significantly promoted cell proliferation, migration, invasion, spheroid formation and repressed anticancer drug-induced apoptosis in vitro. CRISPR-Cas9 system mediated miR-10a knockout in cancer GC showed opposite phenotype compared to miR-10a overexpressed cancer GC. By using xenograft and orthotropic models, the onco?genic role of miR-10a was further confirmed in vivo. RNA-seq, Western blot, luciferase reporter assay and FISH were used to identified PTEN/TET2 as direct functional targets of miR-10a in cancer GC; Akt and Wnt were found as two associated signaling pathways of miR- 10a in cancer GC. CONCLUSION Taken together, our results demonstrate that the miR-10a is positively involved in development of GCT.

Expression of TET2 and DNMT3A in peripheral T cell lymphoma and their significance / 临床与实验病理学杂志

Purpose To investigate the expression of TET2 and DNMT3A in patients with peripheral T cell lymphoma (PTCL) and the relationship to immunophenotypes of PTCL.Methods Using a panel of immunohistochemical markers (CD3,CD4,CD10,BCL-6,CXCL-13,CD30,ALK),all cases of PTCLs were further divided into four groups,including angioimmunoblastic T cell lymphoma (AITL),peripheral T cell lymphoma,not otherwise specified (PTCL-NOS),anaplastic lymphoma kinase negative anaplastic large cell lymphoma (ALK-ALCL) and anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALK + ALCL).The expression of TET2 and DNMT3A in 89 cases of PTCL was detected by immunohistochemical analysis.Results 89 cases were divide into four subtypes,AITL (36/89),PTCL-NOS (26/89),ALKALCL (18/89),and ALK + ALCL (9/89).Immunohistochemistry staining revealed higher cytoplasmic expression of TET2 and DNMT3A in AITL than that of in PTCL-NOS and ALCL (P ＜ 0.05).And the nuclear expression of DNMT3A in patients with AITL was higher than that of PTCL-NOS and ALCL (P ＜ 0.05).The cytoplasmic expression of TET2 was positively related with both cytoplasmic and nuclear expression of DNMT3A in patients with AITL (P ＜ 0.05).Conclusion TET2 combined with DNMT3A could be used as markers in AITL diagnosis,which could provide new strategy for AITL diagnosis.