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Claudia Gebhard, Dagmar Glatz, Lucia Schwarzfischer, Julia Wimmer, Sebastian Stasik, Margit Nuetzel, Daniel Heudobler, Reinhard Andreesen, Gerhard Ehninger, Christian Thiede, Michael Rehli
Malignant transformation is frequently associated with disease-specific epigenetic alterations, but the underlying mechanisms and pathophysiological consequences remain poorly understood. Here, we used global comparative DNA methylation profiling at CG-rich regions of 27 acute myeloid leukemia (AML) samples to select a subset of aberrantly methylated CG-rich regions (~400 regions, ~15,000 CpGs) for quantitative DNA methylation profiling in a large cohort of AML patients (n = 196) using MALDI-TOF analysis of bisulfite-treated DNA...
June 20, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Jing Qu, Lanyan Zhu, Zijing Zhou, Ping Chen, Shuyan Liu, Morgan L Locy, Victor J Thannickal, Yong Zhou
RATIONALE: Desmoplakin (DSP), the most abundant component of desmosomes which maintain the mechanical integrity of epithelium, is a GWAS-identified genetic risk locus in human idiopathic pulmonary fibrosis (IPF). IPF subjects express a significantly higher level of DSP than control subjects. OBJECTIVES: Determine potential mechanisms by which DSP is regulated in lung fibrosis Methods: Matrigel-coated soft and stiff polyacrylamide gels were made to simulate the stiffness of normal and fibrotic lungs...
June 20, 2018: American Journal of Respiratory and Critical Care Medicine
Christian Pflueger, Dennis Tan, Tessa Swain, Trung Viet Nguyen, Jahnvi Pflueger, Christian Nefzger, Jose M Polo, Ethan Ford, Ryan Lister
DNA methylation is a covalent modification of the genome that plays important roles in genome regulation and vertebrate development. Although detection of this modification in the genome has been possible for several decades, the ability to deliberately and specifically manipulate local DNA methylation states in the genome has been extremely limited. Consequently, this has impeded the direct determination of the consequence of DNA methylation on transcriptional regulation and transcription factor binding in the native chromatin context...
June 15, 2018: Genome Research
Sun Wu, Yifeng Dai, Yuan Zhang, Xiufeng Wang, Lihua Wang, Dong Ma, Lingxiu Zhang, Yifan Pang, Yang Jiao, Mingshan Niu, Kailin Xu, Xiaoyan Ke, Jinlong Shi, Zhiheng Cheng, Lin Fu
The mutational spectrum and prognostic stratification of intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML, are unclear. In order to explore the prognostic significance of the mutational spectrum in IR-AML, 106 IR-AML patients were collected from The Cancer Genome Atlas database. Sixty-two patients underwent chemotherapy-only, forty-four proceeded to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Fifty-five patients had more than five recurrent genetic mutations...
June 15, 2018: Cancer Gene Therapy
Victoria V Prassek, Maja Rothenberg-Thurley, Maria C Sauerland, Tobias Herold, Hanna Janke, Bianka Ksienzyk, Nikola P Konstandin, Dennis Goerlich, Utz Krug, Andreas Faldum, Wolfgang E Berdel, Bernhard Wörmann, Jan Braess, Stephanie Schneider, Marion Subklewe, Stephan K Bohlander, Wolfgang Hiddemann, Karsten Spiekermann, Klaus H Metzeler
Acute myeloid leukemia is a disease of the elderly (median age at diagnosis, 65-70 years). The prognosis of older acute myeloid leukemia patients is generally poor. While genetic markers have become important tools for risk stratification and treatment selection in young and middle-aged acute myeloid leukemia patients, their applicability in very old patients is less clear. We sought to validate existing genetic risk classifications systems and identify additional factors associated with outcomes in intensively treated acute myeloid leukemia patients aged ≥75 years...
June 14, 2018: Haematologica
Katrina Tatton-Brown, Anna Zachariou, Chey Loveday, Anthony Renwick, Shazia Mahamdallie, Lise Aksglaede, Diana Baralle, Daniela Barge-Schaapveld, Moira Blyth, Mieke Bouma, Jeroen Breckpot, Beau Crabb, Tabib Dabir, Valerie Cormier-Daire, Christine Fauth, Richard Fisher, Blanca Gener, David Goudie, Tessa Homfray, Matthew Hunter, Agnete Jorgensen, Sarina G Kant, Cathy Kirally-Borri, David Koolen, Ajith Kumar, Anatalia Labilloy, Melissa Lees, Carlo Marcelis, Catherine Mercer, Cyril Mignot, Kathryn Miller, Katherine Neas, Ruth Newbury-Ecob, Daniela T Pilz, Renata Posmyk, Carlos Prada, Keri Ramsey, Linda M Randolph, Angelo Selicorni, Deborah Shears, Mohnish Suri, I Karen Temple, Peter Turnpenny, Lionel Val Maldergem, Vinod Varghese, Hermine E Veenstra-Knol, Naomi Yachelevich, Laura Yates, Nazneen Rahman
Tatton-Brown-Rahman syndrome (TBRS; OMIM 615879), also known as the DNMT3A-overgrowth syndrome, is an overgrowth intellectual disability syndrome first described in 2014 with a report of 13 individuals with constitutive heterozygous DNMT3A variants. Here we have undertaken a detailed clinical study of 55 individuals with de novo DNMT3A variants, including the 13 previously reported individuals. An intellectual disability and overgrowth were reported in >80% of individuals with TBRS and were designated major clinical associations...
2018: Wellcome Open Research
Lambert Busque, Manuel Buscarlet, Luigina Mollica, Ross L Levine
The recent characterization of clonal hematopoiesis in a large segment of the aging population has raised tremendous interest and concern alike. Mutations have been documented in genes associated with hematological cancers and in non-driver candidates. These mutations are present at low frequency in the majority of individuals after middle-age, and principally affect the epigenetic modifiers DNMT3A and TET2. In 10%-40% of cases, the clone will progress to meet the diagnostic criteria for Clonal Hematopoiesis of Indeterminate Potential, which is associated with an increased risk of hematological cancer and cardiovascular mortality...
June 8, 2018: Stem Cells
Antonio D Barrera, Elina V García, Dora C Miceli
SummaryDuring preimplantation development, embryos are exposed and have the capacity to respond to different growth factors present in the maternal environment. Among these factors, transforming growth factor β1 (TGF-β1) is a well known modulator of embryonic growth and development. However, its action during the first stages of development, when the embryo transits through the oviduct, has not been yet elucidated. The objective of the present study was to examine the effect of early exposure to exogenous TGF-β1 on embryo development and expression of pluripotency (OCT4, NANOG) and DNA methylation (DNMT1, DNMT3A, DNMT3B) genes in bovine embryos produced in vitro...
June 8, 2018: Zygote: the Biology of Gametes and Early Embryos
Mrinal M Patnaik, Ayalew Tefferi
DISEASE OVERVIEW: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (∼15%-20% over 3-5 years). DIAGNOSIS: Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 × 109 /L; monocytes ≥10%), along with bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ∼ 30% of patients, while >90% have gene mutations...
June 2018: American Journal of Hematology
Zhiren Zhang, Yunqing Cao, Yanhui Zhai, Xiaoling Ma, Xinglan An, Sheng Zhang, Ziyi Li
MicroRNA-29b (miR-29b) is a member of the miR-29 family, which targets DNA methyltransferases (DNMTs) and ten eleven translocation enzymes (TETs), thereby regulating DNA methylation. However, the role of miR-29b in porcine early embryo development has not been reported. In this study, we examined the effects of miR-29b in porcine in vitro fertilization (IVF) embryos to investigate the mechanism by which miR-29b regulated DNA methylation. The interference of miR-29b by its special miRNA inhibitor significantly up-regulated Dnmt3a/b and Tet1 but downregulated Tet2/3; meanwhile it increased DNA methylation levels of the global genome and Nanog promoter region but decreased global DNA demethylation levels...
May 2018: Development, Growth & Differentiation
Junji Koya, Mineo Kurokawa
A current broad spectrum of genomic studies on acute myeloid leukemia (AML) has demonstrated that a gene encoding for DNA methyltransferase, specifically DNA methyltransferase 3 alpha (DNMT3A) is frequently mutated. However, DNMT3A variants are present in elderly healthy individuals and patients with AML in complete remission, which suggests that DNMT3A mutations may contribute to pre-leukemic clonal hematopoiesis. Although DNMT3A mutation has been thought to play a pivotal role in AML pathogenesis through the loss of DNA methylation functionality, other potential disease-related mechanisms are poorly understood...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Koichi Ohshima, Hiroaki Miyoshi, Kyohei Yamada
Angioimmunoblastic T-cell lymphoma (AITL) originates from follicular helper T cells and shows variable biological and clinical presentations. The survival rate of patients with AITL did not correlate with T-cell clonality, the presence of EBV-infected cells, EBV-DNA copy number, or IgH rearrangements. However, tumor-associated macrophage/M2 macrophages significantly correlated with worse overall survival (OS). Additionally, patients with composite lymphoma with diffuse large B cell lymphoma and AITL showed worse OS...
2018: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
S Pamela K Shiao, Haiyan Xiao, Lixin Dong, Xiaoling Wang, Kebin Liu, Jinxiong She, Huidong Shi
Despite evidences linking methylation changes in the cancer tissues, little is known about the methylation modification in the peripheral blood. With the current study, we identified differential methylation regions (DMRs) across human genome by collecting the blood samples of colorectal cancer (CRC) patients compared to that of their blood-related family who shared genetic inheritance and environmental influences, and unrelated obese and non-obese controls by accessing publicly available Gene Expression Omnibus data...
May 22, 2018: Oncotarget
Catherine C Coombs, Nancy K Gillis, Xianming Tan, Jonathan S Berg, Markus C Ball, Maria E Balasis, Nathan D Montgomery, Kelly Bolton, Joel S Parker, Tania E Mesa, Sean J Yoder, Michele C Hayward, Nirali M Patel, Kristy L Richards, Christine M Walko, Todd C Knepper, John T Soper, Jared Weiss, Juneko E Grilley-Olson, William Y Kim, Shelton Earp, Ross Levine, Elli Papaemmanuil, Ahmet Zehir, D Neil Hayes, Eric Padron
PURPOSE: In this era of precision-based medicine, for optimal patient care, results reported from commercial next-generation sequencing assays should adequately reflect the burden of somatic mutations in the tumor being sequenced. Here, we sought to determine the prevalence of clonal hematopoiesis leading to possible misattribution of tumor mutation calls on unpaired FoundationMedicine® next-generation sequencing assays. EXPERIMENTAL DESIGN: This was a retrospective cohort study of individuals undergoing next-generation sequencing of solid tumors from two large cancer centers...
June 4, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Tara Nguyen, Gerard E Li, Hui Chen, Charles G Cranfield, Kristine C McGrath, Catherine Anne Gorrie
Electronic cigarette (e-cigarette) use is on the rise worldwide and is particularly attractive to young people and as a smoking substitute by pregnant woman. There is a perception in pregnant woman and women of child-bearing age that the use of e-cigarettes (vaping) is safer than smoking tobacco cigarettes during pregnancy. However, there is little evidence to support this perception. Here, we examined the offspring from mouse dams that had been exposed during and after pregnancy to ambient air (sham) (n=8), e-cigarette aerosols with nicotine (n=8) or e-cigarette aerosols without nicotine (n=8)...
June 4, 2018: Chemical Research in Toxicology
Shilpa S Dhar, Dongyu Zhao, Tao Lin, Bingnan Gu, Khusboo Pal, Sarah J Wu, Hunain Alam, Jie Lv, Kyuson Yun, Vidya Gopalakrishnan, Elsa R Flores, Paul A Northcott, Veena Rajaram, Wei Li, Ali Shilatifard, Roy V Sillitoe, Kaifu Chen, Min Gyu Lee
Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs...
May 18, 2018: Molecular Cell
Hong Wang, Rui Guo, Zhonghua Du, Ling Bai, Lingyu Li, Jiuwei Cui, Wei Li, Andrew R Hoffman, Ji-Fan Hu
The CRISPR-associated Cas9 system can modulate disease-causing alleles both in vivo and ex vivo, raising the possibility of therapeutic genome editing. In addition to gene targeting, epigenetic modulation by the catalytically inactive dCas9 may also be a potential form of cancer therapy. Granulin (GRN), a potent pluripotent mitogen and growth factor that promotes cancer progression by maintaining self-renewal of hepatic stem cancer cells, is upregulated in hepatoma tissues and is associated with decreased tumor survival in patients with hepatoma...
June 1, 2018: Molecular Therapy. Nucleic Acids
Yan-Long Jia, Xiao Guo, Jiang-Tao Lu, Xiao-Yin Wang, Le-Le Qiu, Tian-Yun Wang
CHO cells are the preferred host for the production of complex pharmaceutical proteins in the biopharmaceutical industry, and genome engineering of CHO cells would benefit product yield and stability. Here, we demonstrated the efficacy of a Dnmt3a-deficient CHO cell line created by CRISPR/Cas9 genome editing technology through gene disruptions in Dnmt3a, which encode the proteins involved in DNA methyltransferases. The transgenes, which were driven by the 2 commonly used CMV and EF1α promoters, were evaluated for their expression level and stability...
May 30, 2018: Journal of Cellular and Molecular Medicine
Xiao Lin, Xu Feng, Rong-Rong Cui, Dan Xiong, Jia-Yu Zhong, Ting Zhu, Fuxingzi Li, Feng Wu, Xu-Biao Xie, Min-Zhi Mao, Xiao-Bo Liao, Ling-Qing Yuan
Arterial calcification is a common cardiovascular disease, which initiates from a process of osteoblastic differentiation of VSMCs. Accumulating evidence has demonstrated that microRNAs play an important role in regulating arterial calcification. Our results showed that miR-204 was significantly down-regulated in calcified human renal arteries from uraemia patients, mice calcified arteries due to 5/6 nephrectomy with a high phosphate diet (5/6 NTP) and VSMCs induced by high phosphate. The overexpression of miR-204 alleviated the osteoblastic differentiation of VSMCs...
May 29, 2018: Endocrinology
Chunfang Zhao, Xin Li, Bo Han, Lujiang Qu, Changjun Liu, Jiuzhou Song, Ling Lian, Ning Yang
Marek's disease is an oncogenic and lymphoproliferative disease of chickens caused by Marek's disease virus. Hypermethylation or hypomethylation of CpG islands in gene promoter region are involved in the initiation and progression of carcinogenesis. In this study, we analyzed differential methylation levels of upstream region of gga-miR-130b-3p gene between Marek's disease virus-infected tumorous and non-infected spleens. Around the upstream 1 kb of gga-miR-130b-3p gene, two amplicons were designed that covered 616 bp...
May 11, 2018: Oncotarget
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