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https://www.readbyqxmd.com/read/29351814/setdb1-prevents-tet2-dependent-activation-of-iap-retroelements-in-na%C3%A3-ve-embryonic-stem-cells
#1
Özgen Deniz, Lorenzo de la Rica, Kevin C L Cheng, Dominik Spensberger, Miguel R Branco
BACKGROUND: Endogenous retroviruses (ERVs), which are responsible for 10% of spontaneous mouse mutations, are kept under control via several epigenetic mechanisms. The H3K9 histone methyltransferase SETDB1 is essential for ERV repression in embryonic stem cells (ESCs), with DNA methylation also playing an important role. It has been suggested that SETDB1 protects ERVs from TET-dependent DNA demethylation, but the relevance of this mechanism for ERV expression remains unclear. Moreover, previous studies have been performed in primed ESCs, which are not epigenetically or transcriptionally representative of preimplantation embryos...
January 19, 2018: Genome Biology
https://www.readbyqxmd.com/read/29343972/targeting-histone-methyltransferase-and-demethylase-in-acute-myeloid-leukemia-therapy
#2
REVIEW
Germana Castelli, Elvira Pelosi, Ugo Testa
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome...
2018: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29331774/the-synergy-of-vitamin-c-with-decitabine-activates-tet2-in-leukemic-cells-and-significantly-improves-overall-survival-in-elderly-patients-with-acute-myeloid-leukemia
#3
Huihui Zhao, Huayuan Zhu, Jiayu Huang, Yu Zhu, Ming Hong, Han Zhu, Jingjing Zhang, Shan Li, Lijia Yang, Yun Lian, Shuai Wang, Jianping Mao, Yaoyu Chen, Jianyong Li, Sixuan Qian
BACKGROUND: Decitabine is widely used in the treatment of acute myeloid leukemia (AML) in elderly patients. Low-dose Vitamin C has also been indicated to induce DNA demethylation at the cellular level. However, little is known whether low-dose Vitamin C has a synergistic effect with decitabine in clinic. METHODS: The effect of combined low-dose Vitamin C and decitabine on cell proliferation, the cell cycle, apoptosis and the expression level and activity of TET2 was investigated in HL60 and NB4 human leukemic cells...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29331390/the-tet2-e-cadherin-%C3%AE-catenin-regulatory-loop-confers-growth-and-invasion-in-hepatocellular-carcinoma-cells
#4
Guohua Yang, Xiang Zeng, Mengchuan Wang, Aiguo Wu
The poor outcome of hepatocellular carcinoma (HCC) is mainly due to the development of fast growth, invasion and metastasis. The role of TET2 has been implicated in some cancer types, but its role and mechanisms in HCC remains elusive. In this study, our findings indicated that TET2 expression frequently increased in HCC and that TET2 expressional upregulation correlated with HCC progression. TET2 knockdown inhibited HCC cells proliferation in vitro and growth in vivo, and inhibited the invasion potential of HCC cells...
January 10, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29316957/evaluating-the-breast-cancer-predisposition-role-of-rare-variants-in-genes-associated-with-low-penetrance-breast-cancer-risk-snps
#5
Na Li, Simone M Rowley, Ella R Thompson, Simone McInerny, Lisa Devereux, Kaushalya C Amarasinghe, Magnus Zethoven, Richard Lupat, David Goode, Jason Li, Alison H Trainer, Kylie L Gorringe, Paul A James, Ian G Campbell
BACKGROUND: Genome-wide association studies (GWASs) have identified numerous single-nucleotide polymorphisms (SNPs) associated with small increases in breast cancer risk. Studies to date suggest that some SNPs alter the expression of the associated genes, which potentially mediates risk modification. On this basis, we hypothesised that some of these genes may be enriched for rare coding variants associated with a higher breast cancer risk. METHODS: The coding regions and exon-intron boundaries of 56 genes that have either been proposed by GWASs to be the regulatory targets of the SNPs and/or located < 500 kb from the risk SNPs were sequenced in index cases from 1043 familial breast cancer families that previously had negative test results for BRCA1 and BRCA2 mutations and 944 population-matched cancer-free control participants from an Australian population...
January 9, 2018: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/29312564/azacitidine-combined-with-the-selective-flt3-kinase-inhibitor-crenolanib-disrupts-stromal-protection-and-inhibits-expansion-of-residual-leukemia-initiating-cells-in-flt3-itd-aml-with-concurrent-epigenetic-mutations
#6
Anne-Kathrin Garz, Saskia Wolf, Sonja Grath, Verena Gaidzik, Stefan Habringer, Binje Vick, Martina Rudelius, Christoph Ziegenhain, Sylvia Herold, Marie-Theresa Weickert, Martha Smets, Christian Peschel, Robert A J Oostendorp, Sebastian Bultmann, Irmela Jeremias, Christian Thiede, Konstanze Döhner, Ulrich Keller, Katharina S Götze
Effectively targeting leukemia-initiating cells (LIC) in FLT3-ITD-mutated acute myeloid leukemia (AML) is crucial for cure. Tyrosine kinase inhibitors (TKI) have limited impact as single agents, failing to eradicate LIC in the bone marrow. Using primary AML samples and a patient-derived xenograft model, we investigated whether combining the FLT3-selective TKI crenolanib with the hypomethylating agent azacitidine (AZA) eliminates FLT3-ITD LIC and whether efficacy of this combination depends on co-existing mutations...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29309772/gene-mutation-patterns-of-chinese-acute-myeloid-leukemia-patients-by-targeted-next-generation-sequencing-and-bioinformatic-analysis
#7
Xiaoyu Han, Wei Li, Na He, Panpan Feng, Yihua Pang, Chunyan Ji, Daoxin Ma
PURPOSES: The conventional risk stratification of acute myeloid leukemia (AML), based on cytogenetics, cannot meet the demand for accurate prognostic evaluations. In recent years, gene mutations are found to be potential markers for more accurate risk stratification, but reports on mutation screening of Chinese AML are limited. We aim to display the mutation patterns of Chinese AML patients, reveal the genotype-phenotype correlation and make a comparison with Caucasians patients. METHODS: Genome DNA from 78 patients' bone marrow were extracted for targeted gene mutation panel by next-generation sequencing (NGS) technology...
January 5, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
https://www.readbyqxmd.com/read/29306105/distinct-gene-alterations-with-a-high-percentage-of-myeloperoxidase-positive-leukemic-blasts-in-de-novo-acute-myeloid-leukemia
#8
Rena Kamijo, Hidehiro Itonaga, Rika Kihara, Yasunobu Nagata, Tomoko Hata, Norio Asou, Shigeki Ohtake, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Seishi Ogawa, Tomoki Naoe, Hitoshi Kiyoi, Yasushi Miyazaki
The myeloperoxidase (MPO)-positivity of blasts in bone marrow smears is an important marker for not only the diagnosis, but also the prognosis of acute myeloid leukemia (AML). To investigate the relationship between genetic alterations and MPO-positivity, we performed targeted sequencing for 51 genes and 10 chimeric gene transcripts in 164 newly diagnosed de novo AML patients; 107 and 57 patients were classified as AML with >50% MPO-positive blasts (MPO-high group) and ≤50% MPO-positive blasts, (MPO-low group), respectively...
January 2, 2018: Leukemia Research
https://www.readbyqxmd.com/read/29296817/runx1-regulates-site-specificity-of-dna-demethylation-by-recruitment-of-dna-demethylation-machineries-in-hematopoietic-cells
#9
Takahiro Suzuki, Yuri Shimizu, Erina Furuhata, Shiori Maeda, Mami Kishima, Hajime Nishimura, Saaya Enomoto, Yoshihide Hayashizaki, Harukazu Suzuki
RUNX1 is an essential master transcription factor in hematopoietic development and plays important roles in immune functions. Although the gene regulatory mechanism of RUNX1 has been characterized extensively, the epigenetic role of RUNX1 remains unclear. Here, we demonstrate that RUNX1 contributes DNA demethylation in a binding site-directed manner in human hematopoietic cells. Overexpression analysis of RUNX1 showed the RUNX1-binding site-directed DNA demethylation. The RUNX1-mediated DNA demethylation was also observed in DNA replication-arrested cells, suggesting an involvement of active demethylation mechanism...
September 12, 2017: Blood Advances
https://www.readbyqxmd.com/read/29291002/mutations-in-the-dna-methylation-pathway-and-number-of-driver-mutations-predict-response-to-azacitidine-in-myelodysplastic-syndromes
#10
M Teresa Cedena, Inmaculada Rapado, Alejandro Santos-Lozano, Rosa Ayala, Esther Onecha, María Abaigar, Esperanza Such, Fernando Ramos, José Cervera, María Díez-Campelo, Guillermo Sanz, Jesús Hernández Rivas, Alejandro Lucía, Joaquin Martínez-López
We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0...
December 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/29290626/tet2-loss-dysregulates-the-behavior-of-bone-marrow-mesenchymal-stromal-cells-and-accelerates-tet2-driven-myeloid-malignancy-progression
#11
Rong Li, Yuan Zhou, Zeng Cao, Lin Liu, Jinhuan Wang, Zizhen Chen, Wen Xing, Shi Chen, Jie Bai, Weiping Yuan, Tao Cheng, Mingjiang Xu, Feng-Chun Yang, Zhigang Zhao
TET2 is a methylcytosine dioxygenase that regulates cytosine hydroxymethylation. Although there are extensive data implicating a pivotal role of TET2 in hematopoietic stem/progenitor cells (HSPCs), the importance of TET2 in bone marrow mesenchymal stromal cells (BMSCs) remains unknown. In this study, we show that loss of TET2 in BMSCs increases cell proliferation and self-renewal and enhances osteoblast differentiation potential of BMSCs, which may in turn alter their behavior in supporting HSPC proliferation and differentiation...
January 9, 2018: Stem Cell Reports
https://www.readbyqxmd.com/read/29288910/3q26-evi1-rearrangement-in-myelodysplastic-myeloproliferative-neoplasms-an-early-event-associated-with-a-poor-prognosis
#12
Zhihong Hu, Shimin Hu, Changsheng Ji, Zhenya Tang, Beenu Thakral, Sanam Loghavi, L Jeffrey Medeiros, Wei Wang
3q26.2/EVI1 rearrangements resulting in EVI1 overexpression play an important role in leukemogenesis and are associated with treatment resistance and a poorer prognosis in patients with acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia and BCR-ABL negative myeloproliferative neoplasms. In this study, we aim to explore the clinicopathological features of myelodysplastic/myeloproliferative (MDS/MPN) neoplasms with 3q26.2/EVI1 rearrangements and determine the potential impact of these cytogenetic abnormalities on treatment response and survival...
December 23, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29286410/an-engineered-split-tet2-enzyme-for-chemical-inducible-dna-hydroxymethylation-and-epigenetic-remodeling
#13
Minjung Lee, Yubin Zhou, Yun Huang
DNA methylation is a stable and heritable epigenetic modification in the mammalian genome and is involved in regulating gene expression to control cellular functions. The reversal of DNA methylation, or DNA demethylation, is mediated by the ten-eleven translocation (TET) protein family of dioxygenases. Although it has been widely reported that aberrant DNA methylation and demethylation are associated with developmental defects and cancer, how these epigenetic changes directly contribute to the subsequent alteration in gene expression or disease progression remains unclear, largely owing to the lack of reliable tools to accurately add or remove DNA modifications in the genome at defined temporal and spatial resolution...
December 18, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29285667/epigenetic-erasing-and-pancreatic-differentiation-of-dermal-fibroblasts-into-insulin-producing-cells-are-boosted-by-the-use-of-low-stiffness-substrate
#14
Georgia Pennarossa, Rosaria Santoro, Elena F M Manzoni, Maurizio Pesce, Fulvio Gandolfi, Tiziana A L Brevini
Several studies have demonstrated the possibility to revert differentiation process, reactivating hypermethylated genes and facilitating cell transition to a different lineage. Beside the epigenetic mechanisms driving cell conversion processes, growing evidences highlight the importance of mechanical forces in supporting cell plasticity and boosting differentiation. Here, we describe epigenetic erasing and conversion of dermal fibroblasts into insulin-producing cells (EpiCC), and demonstrate that the use of a low-stiffness substrate positively influences these processes...
December 28, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/29285580/bone-marrow-findings-in-blast-phase-of-polycythemia-vera
#15
Juliana E Hidalgo López, Adrian Carballo-Zarate, Srdan Verstovsek, Sa A Wang, Shimin Hu, Shaoying Li, Jie Xu, Wenli Zuo, Zhenya Tang, C Cameron Yin, L Jeffrey Medeiros, Carlos E Bueso-Ramos, Guilin Tang
Approximately 10% of patients with polycythemia vera (PV) transform to acute leukemia (blast phase) at 10 years after initial diagnosis of PV. The bone marrow pathologic, cytogenetic, and molecular features of blast phase have not been well characterized. In this study, we reviewed 422 PV patients over a period of 11 years and identified 58 patients who developed acute myeloid leukemia (blast phase) during the course of disease. We found that blast phase of PV was characterized by overt myelodysplasia (n = 51, 88%); moderate to severe myelofibrosis (33 of 45, 73%); an abnormal karyotype (n = 51, 88%) that was often complex karyotype (n = 42, 72%); and gene mutations involving TP53 (55%), TET2 (27%), and DNMT3A (25%)...
December 28, 2017: Annals of Hematology
https://www.readbyqxmd.com/read/29285192/ten-eleven-translocation-1-dysfunction-reduces-5-hydroxymethylcytosine-expression-levels-in-gastric-cancer-cells
#16
Kuo-Chiang Wang, Chi-Hsiang Kang, Chung-Yu Tsai, Nan-Hua Chou, Ya-Ting Tu, Guan-Cheng Li, Hing-Chung Lam, Shiuh-Inn Liu, Po-Min Chang, Yan-Hwai Lin, Kuo-Wang Tsai
A sixth base, 5-hydroxymethylcytosine (5hmC), is formed by the oxidation of 5-methylcytosine (5mC) via the catalysis of the ten-eleven translocation (TET) protein family in cells. Expression levels of 5hmC are frequently depleted during carcinogenesis. However, the detailed mechanisms underlying the depletion of 5hmC expression in gastric cancer cells remains unclear, and further research is required. The present study examined the expression levels of 5mC and 5hmC and the expression levels of TET1 and TET2 in gastric cancer tissues using immunohistochemistry...
January 2018: Oncology Letters
https://www.readbyqxmd.com/read/29282357/risk-factors-for-arterial-versus-venous-thrombosis-in-polycythemia-vera-a-single-center-experience-in-587-patients
#17
S Cerquozzi, D Barraco, T Lasho, C Finke, C A Hanson, R P Ketterling, A Pardanani, N Gangat, A Tefferi
In a recent International Working Group on Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) study, prior arterial events and hypertension were predictors of subsequent arterial thrombosis whereas prior venous events and age ≥65 years predicted venous thrombosis in polycythemia vera (PV). In the current study, we sought to validate the above findings and identify additional predictors of arterial versus venous thrombosis. At a median follow up of 109 months, thrombosis after diagnosis occurred in 128 (22%) patients; 82 (14%) arterial and 57 (10%) venous events...
December 27, 2017: Blood Cancer Journal
https://www.readbyqxmd.com/read/29279549/recent-progress-in-the-understanding-of-angioimmunoblastic-t-cell-lymphoma
#18
Manabu Fujisawa, Shigeru Chiba, Mamiko Sakata-Yanagimoto
Angioimmunoblastic T-cell lymphoma (AITL) has been classified as a subtype of mature T-cell neoplasms. The recent revision of the WHO classification proposed a new category of nodal T-cell lymphoma with follicular helper T (TFH)-cell phenotype, which was classified into three diseases: AITL, follicular T-cell lymphoma, and nodal peripheral T-cell lymphoma with TFH phenotype. These lymphomas are defined by the expression of TFH-related antigens, CD279/PD-1, CD10, BCL6, CXCL13, ICOS, SAP, and CXCR5. Although recurrent mutations in TET2, IDH2, DNMT3A, RHOA, and CD28, as well as gene fusions, such as ITK-SYK and CTLA4-CD28, were not diagnostic criteria, they may be considered as novel criteria in the near future...
2017: Journal of Clinical and Experimental Hematopathology: JCEH
https://www.readbyqxmd.com/read/29275866/cooperative-epigenetic-remodeling-by-tet2-loss-and-nras-mutation-drives-myeloid-transformation-and-mek-inhibitor-sensitivity
#19
Hiroyoshi Kunimoto, Cem Meydan, Abbas Nazir, Justin Whitfield, Kaitlyn Shank, Franck Rapaport, Rebecca Maher, Elodie Pronier, Sara C Meyer, Francine E Garrett-Bakelman, Martin Tallman, Ari Melnick, Ross L Levine, Alan H Shih
Mutations in epigenetic modifiers and signaling factors often co-occur in myeloid malignancies, including TET2 and NRAS mutations. Concurrent Tet2 loss and NrasG12D expression in hematopoietic cells induced myeloid transformation, with a fully penetrant, lethal chronic myelomonocytic leukemia (CMML), which was serially transplantable. Tet2 loss and Nras mutation cooperatively led to decrease in negative regulators of mitogen-activated protein kinase (MAPK) activation, including Spry2, thereby causing synergistic activation of MAPK signaling by epigenetic silencing...
December 13, 2017: Cancer Cell
https://www.readbyqxmd.com/read/29274134/a-distinct-immunophenotype-identifies-a-subset-of-npm1-mutated-aml-with-tet2-or-idh1-2-mutations-and-improved-outcome
#20
Emily F Mason, Frank C Kuo, Robert P Hasserjian, Adam C Seegmiller, Olga Pozdnyakova
Recent work has identified distinct molecular subgroups of acute myeloid leukemia (AML) with implications for disease classification and prognosis. NPM1 is one of the most common recurrently mutated genes in acute myeloid leukemia (AML). NPM1 mutations often co-occur with FLT3-ITDs and mutations in genes regulating DNA methylation, such as DNMT3A, TET2, and IDH1/2. It remains unclear whether these genetic alterations are associated with distinct immunophenotypic findings or affect prognosis. We identified 133 cases of NPM1-mutated AML and correlated sequencing data with immunophenotypic and clinical findings...
December 23, 2017: American Journal of Hematology
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