A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.
Ontology highlight
ABSTRACT:
SUBMITTER: Guan Y
PROVIDER: S-EPMC7935131 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Acute myelogenous leukemia (AML) is a heterogeneous disease characterized by myeloid progenitor cells uncontrolled proliferation gradually replacing normal hematopoiesis. To evaluate Ten Eleven Translocation 2 gene (TET2) single nucleotide polymorphism (SNP) (rs2454206, rs34402524, rs61744960) in AML, and chronic myeloid leukemia (CML) in relation to their disease prognostic criteria. The study included 136 subjects; 52 AML, 54 CML and 30 subjects as control group matched for age and sex. Routine investigations including CBC, bone marrow aspiration, flow cytometry biochemical investigations and cytogenetics and molecular study were performed accordingly. DNA extraction and SNP assay for TET2 gene polymorphism was done using (Thermo-Fisher predesigned SNP, USA) PCR prism 7500. The mean age was 43.4 ± 14.0 years in AML patients, 45.98 ± 15.7 years in CML patients and 39.3 ± 6.587 years in control group (p > 0.05). The frequency of TET2 SNP rs 34402524 ranged from heterozygous to homozygous in both AML (46%, 54%) and CML (48%, 46.2%) groups but was mainly homozygous among the control (80%) group (p = 0.012). TET2 SNP rs 2454206 was mainly wild in CML (65.4%) and control (63.3%) groups compared to AML as wild was only in (46%) and heterozygous in (44%) with only 10% being homozygous (p = 0.046). TET2 SNP rs 61744960 showed a homozygous pattern among all three group (AML CML and control) showing no statistical significance (p = 0.528). Eventhough, higher non responders to treatment were among homozygous and heterozygous groups yet, response to therapy as respect to specific TET2 SNP showed no significant variation (p > 0.05). TET2 SNP in CML cases did not alter the prognostic criteria as no statistical significance was noted (p > 0.05) except for TET2 SNP rs 34402524 where homozygous cases had larger spleen size (p = 0.019). TET2 SNP is common in Egyptian myeloid neoplasm. This is the first study in this field and further studies are recommended to investigate TET2 and relation to other hematological malignancies and leukemogenesis transformation.
| S-EPMC7042427 | biostudies-literature
Project description:New 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.TET2 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.Our results suggest that TET2 expression is reduced in MDS/AML patients, independently of mutational status.
| S-EPMC4793581 | biostudies-literature
Project description:TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.
| S-EPMC3003755 | biostudies-literature
Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT myeloid neoplasia (MN), clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.
| S-EPMC7477582 | biostudies-literature
Project description:Somatic TET2 mutations (TET2 MT) are frequent in myeloid neoplasia (MN), particularly chronic myelomonocytic leukemia (CMML). TET2 MT includes mostly loss-of-function/hypomorphic hits. Impaired TET2 activity skews differentiation of hematopoietic stem cells toward proliferating myeloid precursors. This study was prompted by the observation of frequent biallelic TET2 gene inactivations (biTET2 i ) in CMML. We speculated that biTET2 i might be associated with distinct clinicohematological features. We analyzed TET2 MT in 1045 patients with MN. Of 82 biTET2 i cases, 66 were biTET2 MT, 13 were hemizygous TET2 MT, and 3 were homozygous TET2 MT (uniparental disomy); the remaining patients (denoted biTET2 - hereafter) were either monoallelic TET2 MT (n = 96) or wild-type TET2 (n = 823). Truncation mutations were found in 83% of biTET2 i vs 65% of biTET2 - cases (P = .02). TET2 hits were founder lesions in 72% of biTET2 i vs 38% of biTET2 - cases (P < .0001). In biTET2 i , significantly concurrent hits included SRSF2 MT (33%; P < .0001) and KRAS/NRAS MT (16%; P = .03) as compared with biTET2 - When the first TET2 hit was ancestral in biTET2 i , the most common subsequent hits affected a second TET2 MT, followed by SRSF2 MT, ASXL1 MT, RAS MT, and DNMT3A MT BiTET2 i patients without any monocytosis showed an absence of SRSF2 MT BiTET2 i patients were older and had monocytosis, CMML, normal karyotypes, and lower-risk disease compared with biTET2 - patients. Hence, while a second TET2 hit occurred frequently, biTET2 i did not portend faster progression but rather determined monocytic differentiation, consistent with its prevalence in CMML. Additionally, biTET2 i showed lower odds of cytopenias and marrow blasts (≥5%) and higher odds of myeloid dysplasia and marrow hypercellularity. Thus, biTET2 i might represent an auxiliary assessment tool in MN.
| S-EPMC6373752 | biostudies-literature
Project description:Ten-Eleven-Translocation-2 (Tet2) is a DNA methylcytosine dioxygenase that functions as a tumor suppressor in hematopoietic malignancies. We examined the role of Tet2 in tumor-tissue myeloid cells and found that Tet2 sustains the immunosuppressive function of these cells. We found that Tet2 expression is increased in intratumoral myeloid cells both in mouse models of melanoma and in melanoma patients and that this increased expression is dependent on an IL-1R-MyD88 pathway. Ablation of Tet2 in myeloid cells suppressed melanoma growth in vivo and shifted the immunosuppressive gene expression program in tumor-associated macrophages to a proinflammatory one, with a concomitant reduction of the immunosuppressive function. This resulted in increased numbers of effector T cells in the tumor, and T cell depletion abolished the reduced tumor growth observed upon myeloid-specific deletion of Tet2. Our findings reveal a non-cell-intrinsic, tumor-promoting function for Tet2 and suggest that Tet2 may present a therapeutic target for the treatment of non-hematologic malignancies.
| S-EPMC5710009 | biostudies-literature
Project description:Therapeutic monoclonal antibodies (mAbs) such as antibody-drug conjugates, ligand-receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells-the so-called leukemic stem cells (LSCs) that are highly resistant to most standard drugs-these malignancies frequently relapse and have a high disease-specific mortality. Therefore, combining standard chemotherapy with antileukemic mAbs that specifically target malignant blasts and particularly LSCs or utilizing mAbs that reinforce antileukemic host immunity holds great promise for improving patient outcomes. This review provides an overview of therapeutic mAbs for AML and MDS. Antibody targets, the molecular mechanisms of action, the efficacy in preclinical leukemia models, and the results of clinical trials are discussed. New developments and future studies of therapeutic mAbs in myeloid neoplasms will advance our understanding of the immunobiology of these diseases and enhance current therapeutic strategies.
| S-EPMC5968093 | biostudies-literature
Project description:To characterize target specificity of TETi76, we performed global gene expression analyses of K562TET2+/+ and TET2-/- control cells; TETi76 mimicked expression signatures generated by the loss of TET2 in K562. The addition of Ascorbic Acid (AA), known to enhance TET-dioxygenase activity, counteracted the changes induced by TETi76. In order to study the molecular pathway of synthetic lethality by TET-dioxygenase inhibition, natural TET2-/- mutant cell line SIGM5 was treated with TET inhibitor TETi76 and global gene expression analysis was performed by RNAseq. Result demostrate a significant upregulation of TNT-α signaling and the down regulation of Interferon-α signaling. Interestingly, we also observed significant up-modulation of oxidative stress response pathway genes consistent with the inhibition of dioxygenases. In particular, TETi76 treatment induces 8-fold increase of oxidative stress sensor NQO1 a NRF2 target gene that has been shown earlier to induce pro-apoptotic cell death in cancer cells.
2020-12-03 | GSE162487 | GEO
Project description:Myeloproliferative neoplasms (MPNs) are clinically characterized by the chronic overproduction of differentiated peripheral blood cells and the gradual expansion of malignant intramedullary/extramedullary hematopoiesis. In MPNs mutations in JAK2 MPL or CALR are detected mutually exclusive in more than 90% of cases [1,2]. Mutations in them lead to the abnormal activation of JAK/STAT signaling and the autonomous growth of differentiated cells therefore they are considered as "driver" gene mutations. In addition to the above driver gene mutations mutations in epigenetic regulators such as TET2 DNMT3A ASXL1 EZH2 or IDH1/2 are detected in about 5%-30% of cases respectively [3]. Mutations in TET2 DNMT3A EZH2 or IDH1/2 commonly confer the increased self-renewal capacity on normal hematopoietic stem cells (HSCs) but they do not lead to the autonomous growth of differentiated cells and only exhibit subtle clinical phenotypes [4,6-8,5]. It was unclear how mutations in such epigenetic regulators influenced abnormal HSCs with driver gene mutations how they influenced the disease phenotype or whether a single driver gene mutation was sufficient for the initiation of human MPNs. Therefore we focused on JAK2V617F and loss of TET2-the former as a representative of driver gene mutations and the latter as a representative of mutations in epigenetic regulators-and examined the influence of single or double mutations on HSCs (Lineage(-)Sca-1(+)c-Kit(+) cells (LSKs)) by functional analyses and microarray whole-genome expression analyses [9]. Gene expression profiling showed that the HSC fingerprint genes [10] was statistically equally enriched in TET2-knockdown-LSKs but negatively enriched in JAK2V617F-LSKs compared to that in wild-type-LSKs. Double-mutant-LSKs showed the same tendency as JAK2V617F-LSKs in terms of their HSC fingerprint genes but the expression of individual genes differed between the two groups. Among 245 HSC fingerprint genes 100 were more highly expressed in double-mutant-LSKs than in JAK2V617F-LSKs. These altered gene expressions might partly explain the mechanisms of initiation and progression of MPNs which was observed in the functional analyses [9]. Here we describe gene expression profiles deposited at the Gene Expression Omnibus (GEO) under the accession number GSE62302 including experimental methods and quality control analyses.
| S-EPMC4535894 | biostudies-literature
Project description:Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during Escherichia (E.) coli induced peritonitis. LPS induced Tet2 expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo. Bone marrow-derived macrophages from myeloid Tet2 deficient (Tet2fl/flLysMCre) mice displayed enhanced production of IL-1β, IL-6 and CXCL1 upon stimulation with several Toll-like receptor agonists; similar results were obtained with LPS stimulated alveolar and peritoneal macrophages. Histone deacetylation was involved in the effect of Tet2 on IL-6 production, whilst methylation at the Il6 promoter was not altered by Tet2 deficiency. Tet2fl/flLysMCre mice showed higher IL-6 and TNF levels in bronchoalveolar and peritoneal lavage fluid after intranasal and intraperitoneal LPS administration, respectively, whilst other inflammatory responses were unaltered. E. coli induced stronger production of IL-1β and IL-6 by Tet2 deficient peritoneal macrophages but not in peritoneal lavage fluid of Tet2fl/flLysMCre mice after in vivo intraperitoneal infection. Tet2fl/flLysMCre mice displayed enhanced bacterial growth during E. coli peritonitis, which was associated with a reduced capacity of Tet2fl/flLysMCre peritoneal macrophages to inhibit the growth of E. coli in vitro. Collectively, these data suggest that Tet2 is involved in the regulation of macrophage functions triggered by LPS and during E. coli infection.
| S-EPMC8750455 | biostudies-literature