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https://www.readbyqxmd.com/read/29773648/ten-eleven-translocation-2-demethylates-the-mmp9-promoter-and-its-down-regulation-in-preeclampsia-impairs-trophoblast-migration-and-invasion
#1
Xiaoliang Li, Chunlian Wu, Ying Shen, Ke Wang, Li Tang, Mi Zhou, Ming Yang, Tianying Pan, Xinghui Liu, Wenming Xu
Preeclampsia is the most common clinical disorder in pregnancy and might result from disordered uterine environments caused by epigenetic modifications, including deregulation of DNA methylation/demethylation. Recent research has indicated that 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine (5mC) via oxidation by ten-eleven translocation (TET) enzymes, is involved in DNA methylation-related plasticity. Here, we report that TET2 expression and 5hmC abundance are significantly altered in the placentas from preeclampsia patients...
May 17, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29769727/microbial-signals-drive-pre-leukaemic-myeloproliferation-in-a-tet2-deficient-host
#2
Marlies Meisel, Reinhard Hinterleitner, Alain Pacis, Li Chen, Zachary M Earley, Toufic Mayassi, Joseph F Pierre, Jordan D Ernest, Heather J Galipeau, Nikolaus Thuille, Romain Bouziat, Manuel Buscarlet, Daina L Ringus, Yitang Wang, Ye Li, Vu Dinh, Sangman M Kim, Benjamin D McDonald, Matthew A Zurenski, Mark W Musch, Glaucia C Furtado, Sergio A Lira, Gottfried Baier, Eugene B Chang, A Murat Eren, Christopher R Weber, Lambert Busque, Lucy A Godley, Elena F Verdú, Luis B Barreiro, Bana Jabri
Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies1-7 . In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage1,4,8,9 . However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2-/- mice8,9 and humans with TET2 mutations1,3,5-7 , suggesting that extrinsic non-cell-autonomous factors are required for disease onset...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29769264/rhoa-g17v-is-sufficient-to-induce-autoimmunity-and-promotes-t-cell-lymphomagenesis-in-mice
#3
Samuel Y Ng, Leon Brown, Kristen Stevenson, Tiffany deSouza, Jon C Aster, Abner Louissaint, David M Weinstock
Patients with angioimmunoblastic T-cell lymphoma (AITL) and other peripheral T-cell lymphomas (PTCL) that harbor features of follicular helper T (TFH) cells have a very poor prognosis. These lymphomas commonly present with paraneoplastic autoimmunity and lymphopenia. RhoA G17V mutation is present in 60% of TFH-like lymphomas but its role in tumorigenesis is poorly understood. We generated transgenic mice that express RhoA G17V under the control of murine CD4 regulatory elements at levels comparable to a heterozygous mutation (tgRhoA mice)...
May 16, 2018: Blood
https://www.readbyqxmd.com/read/29768411/cytoskeleton-structure-and-total-methylation-of-mouse-cardiac-and-lung-tissue-during-space-flight
#4
Irina V Ogneva, Sergey S Loktev, Vladimir N Sychev
The purpose of this work was to evaluate the protein and mRNA expression levels of multiple cytoskeletal proteins in the cardiac and lung tissue of mice that were euthanized onboard the United States Orbital Segment of the International Space Station 37 days after the start of the SpaceX-4 mission (September 2014, USA). The results showed no changes in the cytoskeletal protein content in the cardiac and lung tissue of the mice, but there were significant changes in the mRNA expression levels of the associated genes, which may be due to an increase in total genome methylation...
2018: PloS One
https://www.readbyqxmd.com/read/29767839/jak2-v617f-positive-acute-myeloid-leukaemia-aml-a-comparison-between-de-novo-aml-and-secondary-aml-transformed-from-an-underlying-myeloproliferative-neoplasm-a-study-from-the-bone-marrow-pathology-group
#5
Jason Aynardi, Rashmi Manur, Paul R Hess, Seble Chekol, Jennifer J D Morrissette, Daria Babushok, Elizabeth Hexner, Heesun J Rogers, Eric D Hsi, Elizabeth Margolskee, Attilio Orazi, Robert Hasserjian, Adam Bagg
The JAK2 V617F mutation is characteristic of most Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) and occurs rarely in de novo acute myeloid leukaemia (AML). We sought to characterize AMLs that harbour this mutation and distinguish those that arise de novo (AML-DN) from those that reflect transformation of an underlying MPN (AML-MPN). Forty-five patients with JAK2 V617F-mutated AML were identified; 15 were AML-DN and 30 were AML-MPN. AML-MPN cases were more likely to have splenomegaly (P = 0·02), MPN-like megakaryocytes and higher mean JAK2 V617F VAF at diagnosis (P = 0·04)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29764867/3d-fibrin-stiffness-mediates-dormancy-of-tumor-repopulating-cells-via-a-cdc42-driven-tet2-epigenetic-program
#6
Yuying Liu, Jiadi Lv, Xiaoyu Liang, Xiaonan Yin, Le Zhang, Degao Chen, Xun Jin, Roland Fiskesund, Ke Tang, Jingwei Ma, Huafeng Zhang, Wenqian Dong, Siqi Mo, Tianzhen Zhang, Feiran Cheng, Yabo Zhou, Jing Xie, Ning Wang, Bo Huang
Dormancy is recognized as a critical biological event for tumorigenic cells surviving in an extremely harsh environment. Understanding the molecular process of dormancy can unlock novel approaches to tackle cancers. We recently reported that stem-like tumor-repopulating cells (TRC) sense mechanical signals and rapidly proliferate in a 90 Pa soft fibrin matrix. Here we show that a stiff mechanical environment induces TRC dormancy via an epigenetic program initiated by translocation of Cdc42, a cytosolic regulator of mechanotransduction, into the nucleus, where it promotes transcription of hydroxymethylating enzyme Tet2...
May 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29764839/lineage-restriction-analyses-in-chip-indicate-myeloid-bias-for-tet2-and-multipotent-stem-cell-origin-for-dnmt3a
#7
Manuel Buscarlet, Sylvie Provost, Yassamin Feroz Zada, Vincent Bourgoin, Luigina Mollica, Marie-Pierre Dubé, Lambert Busque
We analyzed DNA from PMN (granulocytes), CD14+ (monocytes), CD19+ (B-cells) and CD3+ (T-cells) of 107 individuals with clonal hematopoiesis of indeterminate potential (CHIP) to perform lineage restriction analysis of different gene mutations. Individuals were aged 55 to 96 (mean age: 70.0). Three lineage categories were defined: myeloid (PMN±monocytes), myelolympho-B (myeloid and B-cells), multipotent (myeloid, B and T-cells). Six individuals with aberrant patterns were excluded from analysis. Fifty-six had a single DNMT3A mutation, 24 had a single TET2 mutation, 7 had a single mutation in other genes (JAK2, ASXL1, CBL or TP53), and 14 had multiple mutations...
May 15, 2018: Blood
https://www.readbyqxmd.com/read/29760015/novel-genomic-findings-in-multiple-myeloma-identified-through-routine-diagnostic-sequencing
#8
Georgina L Ryland, Kate Jones, Melody Chin, John Markham, Elle Aydogan, Yamuna Kankanige, Marisa Caruso, Jerick Guinto, Michael Dickinson, H Miles Prince, Kwee Yong, Piers Blombery
AIMS: Multiple myeloma is a genomically complex haematological malignancy with many genomic alterations recognised as important in diagnosis, prognosis and therapeutic decision making. Here, we provide a summary of genomic findings identified through routine diagnostic next-generation sequencing at our centre. METHODS: A cohort of 86 patients with multiple myeloma underwent diagnostic sequencing using a custom hybridisation-based panel targeting 104 genes. Sequence variants, genome-wide copy number changes and structural rearrangements were detected using an inhouse-developed bioinformatics pipeline...
May 14, 2018: Journal of Clinical Pathology
https://www.readbyqxmd.com/read/29735542/pml-recruits-tet2-to-regulate-dna-modification-and-cell-proliferation-in-response-to-chemotherapeutic-agent
#9
Chengli Song, Lina Wang, Xiaoyan Wu, Kai Wang, Dan Xie, Qi Xiao, Songyu Li, Kui Jiang, Lujian Liao, John R Yates, Jiing-Dwan Lee, Qingkai Yang
Aberrant DNA methylation plays a critical role in the development and progression of cancer. Failure to demethylate and to consequently reactivate methylation-silenced genes in cancer contributes to chemotherapeutic resistance, yet the regulatory mechanisms of DNA demethylation in response to chemotherapeutic agents remain unclear. Here, we show that promyelocytic leukemia (PML) recruits ten-eleven translocation dioxygenase 2 (TET2) to regulate DNA modification and cell proliferation in response to chemotherapeutic agents...
May 7, 2018: Cancer Research
https://www.readbyqxmd.com/read/29732371/hippocampal-tet1-and-tet2-expression-and-dna-hydroxymethylation-are-affected-by-physical-exercise-in-aged-mice
#10
Peter Jessop, Maria Toledo-Rodriguez
The function of 5-hydroxymethylcytosine (5hmC) is poorly understood. 5hmC is an epigenetic modification of DNA, resulting from the oxidation of 5-methylcytosine (5mC) by the Fe2+ , and 2-oxoglutarate-dependent, 10-11 translocation methylcytosine dioxygenases (TET1, TET2, and TET3). Recent evidence suggests that, in addition to being an intermediate in active demethylation, 5hmC may also have an epigenetic role. 5hmC is enriched in the adult brain, where it has been implicated in regulating neurogenesis. The rate of adult neurogenesis decreases with age, however physical exercise has been shown to counteract this deficit...
2018: Frontiers in Cell and Developmental Biology
https://www.readbyqxmd.com/read/29728415/crispr-mediated-gene-editing-to-assess-the-roles-of-tet2-and-dnmt3a-in-clonal-hematopoiesis-and-cardiovascular-disease
#11
Soichi Sano, Kousei Ohshima, Ying Wang, Yasufumi Katanasaka, Miho Sano, Kenneth Walsh
<u>Rationale:</u> Clonal hematopoiesis has been associated with increased mortality and cardiovascular disease (CVD). This condition can arise from somatic mutations in pre-leukemic driver genes within hematopoietic stem/progenitor cells (HSPC). Approximately 40 candidate driver genes have been identified, but mutations in only one of these genes, Ten-Eleven Translocation-2 (TET2), has been shown to casually contribute to CVD in murine models. <u>Objective:</u> To develop a facile system to evaluate the disease characteristics of different clonal hematopoiesis driver genes using lentivirus vector and CRISPR/Cas9 methodology...
May 4, 2018: Circulation Research
https://www.readbyqxmd.com/read/29721207/impact-of-mutational-studies-on-the-diagnosis-and-the-outcome-of-high-risk-myelodysplastic-syndromes-and-secondary-acute-myeloid-leukemia-patients-treated-with-5-azacytidine
#12
Marta Cabezón, Joan Bargay, Blanca Xicoy, Olga García, Josep Borrás, Mar Tormo, Sílvia Marcé, Carme Pedro, David Valcárcel, Maria-José Jiménez, Ramón Guàrdia, Laura Palomo, Salut Brunet, Ferran Vall-Llovera, Antoni Garcia, Evarist Feliu, Lurdes Zamora
Myelodysplastic syndromes (MDS) are stem cell disorders caused by various gene abnormalities. We performed targeted deep sequencing in 39 patients with high-risk MDS and secondary acute myeloid leukemia (sAML) at diagnosis and follow-up (response and/or relapse), with the aim to define their mutational status, to establish if specific mutations are biomarkers of response to 5-azacytidine (AZA) and/or may have impact on survival. Overall, 95% of patients harbored at least one mutation. TP53, DNMT3A and SRSF2 were the most frequently altered genes...
April 10, 2018: Oncotarget
https://www.readbyqxmd.com/read/29720492/sustained-clonal-hematopoiesis-by-hla-lacking-hematopoietic-stem-cells-without-driver-mutations-in-aplastic-anemia
#13
Tatsuya Imi, Takamasa Katagiri, Kazuyoshi Hosomichi, Yoshitaka Zaimoku, Viet Hoang Nguyen, Noriharu Nakagawa, Atsushi Tajima, Tetsuichi Yoshizato, Seishi Ogawa, Shinji Nakao
Clonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA- HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA- HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA- HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA- granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years)...
May 8, 2018: Blood Advances
https://www.readbyqxmd.com/read/29707521/evaluation-by-flow-cytometry-of-mature-monocyte-subpopulations-for-the-diagnosis-and-follow-up-of-chronic-myelomonocytic-leukemia
#14
Tiphanie Picot, Carmen Mariana Aanei, Pascale Flandrin Gresta, Pauline Noyel, Sylvie Tondeur, Emmanuelle Tavernier Tardy, Denis Guyotat, Lydia Campos Catafal
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+ /CD16- >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA)...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29705980/blastic-plasmacytoid-dendritic-cell-neoplasm-arising-from-clonal-hematopoiesis
#15
Sakurako Suma, Mamiko Sakata-Yanagimoto, Tran B Nguyen, Keiichiro Hattori, Taiki Sato, Masayuki Noguchi, Yasuhito Nannya, Seishi Ogawa, Rei Watanabe, Manabu Fujimoto, Naoya Nakamura, Manabu Kusakabe, Hidekazu Nishikii, Takayasu Kato, Shigeru Chiba
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of myeloid neoplasm. Clonal evolution in the development of BPDCN remains to be elucidated. In the present study, we examined clonal evolution in a case of BPDCN by analyzing the distribution of gene mutations in tumor cells and non-tumor blood cells. The p.D1129fs and p.K1005fs TET2 mutations, p.P95H SRSF2 mutation, and p.L287fs NPM1 mutation were identified in a skin tumor at diagnosis and peripheral blood mononuclear cells at relapse...
April 28, 2018: International Journal of Hematology
https://www.readbyqxmd.com/read/29705354/effect-of-tet2-on-the-pathogenesis-of-diabetic-nephropathy-through-activation-of-transforming-growth-factor-%C3%AE-1-expression-via-dna-demethylation
#16
Yang Liling, Zhang Qian, Wu Qiong, Wei Yi, Yu Jiawei, Mu Jiao, Zhang Jun, Zeng Wei, Feng Bing
AIMS: Transforming growth factor β1 (TGFβ1) plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). However, the mechanism of its expression and activation induced by high glucose (HG) is still unclear. We mainly explored the role of ten-eleven translocation enzyme-2 (TET2) in regulating TGFβ1 expression in the process of DN. MAIN METHODS: Human mesangial cells (HMCs) and db/db mice were used to analyze the biological effects of hyperglycemia both in vivo and in vitro...
April 26, 2018: Life Sciences
https://www.readbyqxmd.com/read/29702001/clearance-of-somatic-mutations-at-remission-and-the-risk-of-relapse-in-acute-myeloid-leukemia
#17
Kiyomi Morita, Hagop M Kantarjian, Feng Wang, Yuanqing Yan, Carlos Bueso-Ramos, Koji Sasaki, Ghayas C Issa, Sa Wang, Jeffrey Jorgensen, Xingzhi Song, Jianhua Zhang, Samantha Tippen, Rebecca Thornton, Marcus Coyle, Latasha Little, Curtis Gumbs, Naveen Pemmaraju, Naval Daver, Courtney D DiNardo, Marina Konopleva, Michael Andreeff, Farhad Ravandi, Jorge E Cortes, Tapan Kadia, Elias Jabbour, Guillermo Garcia-Manero, Keyur P Patel, P Andrew Futreal, Koichi Takahashi
Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2...
April 27, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29699715/atherosclerosis-and-clonal-hematopoyesis-a-new-risk-factor
#18
José A Páramo Fernández
Recent research has revealed that clonal hematopoyesis of indeterminate potential (CHIP) characterized by the acquisition of somatic mutations in hematopoietic stem cells, is not only a common age-related disorder and a premalignant condition, but it is also associated with the development of atherosclerotic vascular diseases. Mutations in DNMT3A, TET2 and ASXL1 were each individually associated with coronary heart disease, stroke and coronary calcification. Therefore, CHIP emerges as a new risk factor for atherosclerotic vascular pathologies and its detection may be relevant as a new therapeutic target in order to modify the natural course of the disease...
April 23, 2018: Clínica e Investigación en Arteriosclerosis
https://www.readbyqxmd.com/read/29674500/novel-gpr34-and-ccr6-mutation-and-distinct-genetic-profiles-in-malt-lymphomas-of-different-sites
#19
Sarah Moody, Joe Sneath Thompson, Shih-Sung Chuang, Hongxiang Liu, Markus Raderer, George Vassiliou, Iwona Wlodarska, Fangtian Wu, Sergio Cogliatti, Alistair Robson, Margaret Ashton-Key, Yingwen Bi, John Goodlad, Ming-Qing Du
MALT lymphoma originates from a background of diverse chronic inflammatory disorders at various anatomic sites. The genetics underlying its development, particularly in those associated with autoimmune disorders, is poorly characterised. By whole exome sequencing of 21 cases of MALT lymphomas of the salivary gland and thyroid, we have identified recurrent somatic mutations in 2 G-protein coupled receptors (GPR34 and CCR6) not previously reported in human malignancies, 3 genes (PIK3CD, TET2, TNFRSF14) not previously implicated in MALT lymphoma, and a further 2 genes (TBL1XR1, NOTCH1) recently described in MALT lymphoma...
April 19, 2018: Haematologica
https://www.readbyqxmd.com/read/29666467/ascorbic-acid-induces-global-epigenetic-reprogramming-to-promote-meiotic-maturation-and-developmental-competence-of-porcine-oocytes
#20
Xiao-Xia Yu, Yun-Hua Liu, Xiao-Man Liu, Pei-Chao Wang, Shuai Liu, Jia-Kun Miao, Zhi-Qiang Du, Cai-Xia Yang
L-ascorbic acid (Vitamin C) can enhance the meiotic maturation and developmental competence of porcine oocytes, but the underlying molecular mechanism remains obscure. Here we show the role of ascorbic acid in regulating epigenetic status of both nucleic acids and chromatin to promote oocyte maturation and development in pigs. Supplementation of 250 μM L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (AA2P) during in vitro maturation significantly enhanced the nuclear maturation (as indicated by higher rate of first polar body extrusion and increased Bmp15 mRNA level), reduced level of reactive oxygen species, and promoted developmental potency (higher cleavage and blastocyst rates of parthenotes, and decreased Bax and Caspase3 mRNA levels in blastocysts) of pig oocytes...
April 17, 2018: Scientific Reports
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